Download A critical role of interleukin-1 in preterm labor

Cytokine & Growth Factor Reviews 28 (2016) 37–51
Contents lists available at ScienceDirect
Cytokine & Growth Factor Reviews
journal homepage: www.elsevier.com/locate/cytogfr
Survey
A critical role of interleukin-1 in preterm labor
Mathieu Nadeau-Valléea,b , Dima Obarib , Christiane Quinioua , William D. Lubellc ,
David M. Olsond , Sylvie Girarde,* , Sylvain Chemtoba,**
a
Departments of Pediatrics, Ophthalmology and Pharmacology, CHU Sainte-Justine Research Center, Montréal H3T 1C5, Canada
Department of Pharmacology, Université de Montréal, Montréal H3C 3J7, Canada
Department of Chemistry, Université de Montréal, Montréal, Québec H3C 3J7, Canada
d
Departments of Obstetrics and Gynecology, Pediatrics and Physiology, University of Alberta, Edmonton AB TG6 2S2, Canada
e
Departments of Obstetrics and Gynecology, CHU Sainte-Justine Research Centre, Montréal H3T 1C5, Canada
b
c
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 21 September 2015
Received in revised form 24 October 2015
Accepted 3 November 2015
Available online 30 November 2015
Preterm birth (PTB) is a leading cause of neonatal mortality and morbidity worldwide, and represents a
heavy economic and social burden. Despite its broad etiology, PTB has been firmly linked to inflammatory
processes. Pro-inflammatory cytokines are produced in gestational tissues in response to stressors and
can prematurely induce uterine activation, which precedes the onset of preterm labor. Of all cytokines
implicated, interleukin (IL)-1 has been largely studied, revealing a central role in preterm labor. However,
currently approved IL-1-targeting therapies have failed to show expected efficacy in pre-clinical studies
of preterm labor. Herein, we (a) summarize animal and human studies in which IL-1 or IL-1-targeting
therapeutics are implicated with preterm labor, (b) focus on novel IL-1-targeting therapies and diagnostic
tests, and (c) develop the case for commercialization and translation means to hasten their development.
ã 2015 Elsevier Ltd. All rights reserved.
Keywords:
Preterm birth
Preterm labor
Interleukin-1
Inflammation
Infection
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.
Inflammatory cascade leading to PTB and role of interleukin-1 . . .
Overview and mechanism of action of the interleukin-1 system . . . . . . . .
IL-1a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
IL-1b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
IL-1 receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
IL-1Ra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.
Canonical pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.
Role of interleukin-1 in preterm labor . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
IL-1 in preterm labor associated with infection . . . . . . . . . . . . . . . .
Myometrial cells excitability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Polymorphisms in IL-1-related genes and PTB . . . . . . . . . . . . . . . . .
3.3.
Prediction of PTB with levels of IL-1 or IL-1Ra in tissues and fluids
3.4.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
38
38
38
38
39
39
40
41
41
42
42
42
42
Abbreviations: AF, amniotic fluids; AP-1, activator protein-1; CSAIDs, cytokine suppressive anti-inflammatory drugs; DAMPs, damage-associated molecular patterns; ECM,
extracellular matrix; fFN, fetal fibronectin; HPA, hypothalamic-pituitary-adrenal; IKK, IkB kinase; IL, interleukin; IL-1R, interleukin-1 receptor; IL-1Ra, interleukin-1 receptor
antagonist; IL-1RAcP, interleukin-1 receptor accessory protein; IRAK, interleukin-1 receptor-activated protein kinase; LMA, leukocyte migration assay; LPS,
lipopolysaccharide; LTA, lipoteichoic acid; MAPK, mitogen–activated protein kinases; MMPs, matrix metalloproteinases; MYD88, myeloid differentiation primary response
gene 88; NF-kB, nuclear factor-kappa B; NPV, negative prediction value; PAMPs, pathogen-associated molecular patterns; PGHS-2, prostaglandin H synthetase-2; PPV,
positive prediction value; PTB, preterm birth; SAPK, stress–associated protein kinases; TIMP, tissue inhibitor of metalloproteinase; TIR, toll- and IL-1R-like; TLRs, toll-like
receptors; TRAF, tumor necrosis factor–associated factor; TRP, transient receptor potential canonical; UAPs, uterine activation proteins; VEGF, vascular-endothelial growth
factor.
* Corresponding author.
** Corresponding author at: CHU Sainte-Justine, Research Center, Departments of Pediatrics, Ophthalmology and Pharmacology. 3175 Chemin Côte Ste-Catherine, Montréal,
Québec H3T 1C5, Canada. Fax: +1 514 345 4801.
E-mail addresses: [email protected] (S. Girard), [email protected] (S. Chemtob).
http://dx.doi.org/10.1016/j.cytogfr.2015.11.001
1359-6101/ ã 2015 Elsevier Ltd. All rights reserved.
38
4.
5.
6.
7.
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
3.5.
Implication of IL-1 in hormonal regulation related to parturition . . . . . . . . . . . . . . . . . . . . . . . . . .
Modulation of other factors implicated with labor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.6.
IL-1 in normal term labor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Therapies available to counter interleukin-1 action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IL-1 competitive antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
Non-specific NF-kB inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
Cytokine suppressive anti-inflammatory drugs (CSAIDs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.
Inhibition of specific interleukin-1 signals using functional selectivity . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.
Advantages of small noncompetitive peptides over large competitive molecules . . . . . . . . . . . . .
Drawbacks for the development of preventive therapies in PTB . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.
Implications for technology commercialization and translation into clinical application—an unavoidable
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Preterm birth (PTB; delivery before 37 weeks of gestation)
affects 1 out of 10 newborn and is the second leading cause of
infant deaths in the United States and worldwide [1,2]. Major
advances have been made in the past decades, but the etiology of
PTB remains mostly unknown, and to this date no pharmacological
compound has been successful in arresting uterine labor after its
onset. Accordingly, the rate of PTB in the United States has
increased since 1990 (11.72% in 2011 compared to 10.62% in 1990)
suggesting that PTB remains an important clinical challenge
despite advances made [2]. Importantly, annual cost of PTB was
estimated to $26.2 billion in 2005, and this estimation does not
include further health problems that premature infants might
suffer [3].
The onset of labor is a gradual process that begins several days
before delivery with changes in gestational tissues, culminating in
powerful contractions to expulse the conceptus. Term and preterm
labor (PTL; labor before term) share a common (patho) physiological process, including activation of the membranes/decidua
(detachment of the chorioamniotic membranes from the decidua
and rupture of the membrane), uterine contractility (shift from
irregular contractions to functional contractions) and cervical
ripening (dilatation and effacement of the cervix due to changes in
cervical composition and increasing myometrial contractility) [4].
It has been suggested that while term labor is a result of a
physiological activation of this pathway, PTL is on the other hand
the result of a pathological activation of the same process [5–7].
Many causes of PTB have been identified and include infection,
fetal growth disorders, ischemia, uterine over-distension, cervical
incompetence, fetal and maternal stress, hemorrhage, and several
others [8]. For this reason PTB is not seen as a single disease entity,
but is referred to as a syndrome [5,9]. Converging lines of evidences
suggest that inflammation plays a significant role in all labors,
regardless of the presence of infection, other etiology, or timing of
delivery [5,10].
.........
.........
.........
.........
.........
.........
.........
.........
.........
.........
to prevent
.........
.........
....
....
....
....
....
....
....
....
....
....
PTB
....
....
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
42
43
43
43
43
43
44
44
44
44
44
47
47
patterns (DAMPs) or pathogen-associated molecular patterns
(PAMPs). These molecular pattern entities can activate innate
immunity via pattern recognition receptors (PRRs), mostly Tolllike receptors (TLRs). TLRs are expressed abundantly in the
decidua, placenta and membranes throughout pregnancy, in
immune and non-immune cells [18]. Their activation leads to
cytokine and chemokine production and initiates an inflammatory
response characterised by leukocyte activation and transmigration
from peripheral blood to gestational tissues [19]. This leukocyte
extravasation has been observed in the decidua, the cervix, the
placenta, the fetal membranes and the amniotic fluid (AF) in
humans and animal models, and is principally mediated by
cytokines and chemokines, including interleukin (IL)-1, IL-6, IL8 and TNFa [20–27]. As more leukocytes invade the uterus, the
inflammatory response is amplified through increased secretion of
pro-inflammatory mediators. In this context, pro-inflammatory
cytokines can directly trigger the transition from a uterine
quiescent state to a subsequent unscheduled activation of the
uterus (see Fig. 1 for a representation of the inflammatory cascade
leading to PTB, as described above); for this reason, cytokines are
sometimes referred to as uterotrophins (uterine activators).
Several studies have correlated the increase in pro-inflammatory cytokines, including IL-1, with the risk of PTB [28–30]. Since
the discovery that IL-1 expression rises in term deliveries without
infection [31] as well as in preterm deliveries [32], it has been
thought that IL-1 overproduction heralds labor. Not only does IL1 induce labor in various animal species [33,34], but also fetal and
maternal carriers of polymorphisms in genes of the IL-1 system are
associated with PTB in humans [35–37]. Furthermore, an elevated
IL-1b blood concentration in human neonates has been associated
with PTB [38]. For these and other reasons (addressed below),
IL-1 is now considered a key inducer of inflammation in PTL. This
review will focus on the role of IL-1 in PTL, and will discuss the
efficacy of IL-1 receptor antagonists in the context of PTB.
2. Overview and mechanism of action of the interleukin-1
system
1.1. Inflammatory cascade leading to PTB and role of interleukin-1
Birth reflects transition from a pro-pregnancy state and
immunological tolerance towards the fetus allograft to a prolabor, pro-inflammatory state. Notwithstanding the role of
hormones, pro-inflammatory cytokines are thought to orchestrate
the on-time synchronization of the aforementioned physiological
events characterising labor through the induction of uterine
activation proteins (UAPs; including COX-2, prostaglandin F2a
receptor, oxytocin receptor, connexin-43, and others) [11–13]. This
converging inflammatory pathway precedes the onset of both term
and PTL [14–17].
Pathological events leading to PTL are the triggers of
inflammatory stimuli consisting in damage-associated molecular
The interleukin-1 system (illustrated in Fig. 2) is composed of
different proteins including IL-1a, IL-1b, IL-1 receptors and the
endogenous IL-1 receptor antagonist (IL-1Ra). IL-1a and IL-1b
have similar biological effects and bind to the same receptors, but
are encoded by different genes [39].
2.1. IL-1a
The IL-1a precursor (which is synthesized in active form unlike
IL-1b precursor) is constitutively produced in almost all types of
cells in healthy individuals and is released through cell necrosis;
this corresponds to a first step in sterile inflammation. Accordingly,
IL-1a is described as an alarmin (or DAMP) and is fully active in the
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
first few hours after an injury [40,41]. IL-1a is also detected in
activated monocytes as a membrane-bound form. This form does
not require cell lysis to become available for receptor binding.
Binding of either the membrane form (through cell-cell contact) or
the released form to the IL-1 receptor, will result in the initiation of
an inflammatory cascade [42–44]. IL-1a can also be up-regulated
by inflammatory stimuli.
2.2. IL-1b
IL-1b expression is inducible and not constitutive, unlike IL-1a.
IL-1b is mostly produced by hematopoietic cells such as dendritic
cells, blood monocytes and tissue macrophages. The induction of
its transcription is triggered by PAMPs, DAMPs or pro-inflammatory cytokines, including itself. The IL-1b precursor protein
(31 KDa) is cleaved by caspase-1, a cytosolic cysteine protease
part of the NLRP3 inflammasome, into its functional mature form
(17.5 kDa). Inflammatory stimuli such as PAMPs and DAMPs
generate two signals on cells of the innate immune response to
promote IL-1b expression and maturation that are mediated by:
39
(1) TLRs to promote transcriptional induction of pro-IL-1b and; (2)
NOD-like receptors which upon activation oligomerize and
complex with caspase-1 to form the inflammasome which
promotes IL-1b maturation. The active form of IL-1b is then
released in the extracellular space, where it can bind to its receptor
and subsequently initiate or sustain an inflammatory response
[41,43,44]. The maturation process of IL-1b via the inflammasome
is depicted in Fig. 3.
2.3. IL-1 receptors
The IL-1 receptor family comprises 11 receptors and two have
been identified to bind IL-1: IL-1 receptor type 1 (IL-1RI) and IL1 receptor type II (IL-1RII). IL-1RI is ubiquitously expressed and
binds to IL-1 to produce an inflammatory response, whereas IL1RII is found primarily in B lymphocytes, neutrophils and
monocytes and is unable to transduce the signal due to its lack
of a signaling-competent cytoplasmic tail [45–48]. For this reason,
IL-1RII has been identified as a decoy receptor for IL-1, limiting its
action [49]. Binding of IL-1 to IL-1RI induces a conformational
Fig. 1. Inflammatory pathway to preterm labor.
All possible causes of preterm labor (such as infections, genetics, cervical insufficiency . . . ) are thought to invariably lead to an inflammatory cascade wherein cytokines (primarily
IL-1) trigger uterine activation and preterm labor. The initial insult may arise from the environment (infection) or can be maternally-produced by stressed cells (alarmins), the
former being a source of PAMPs and the latter a source of DAMPs. PAMPs and DAMPs can stimulate the innate immune response by activating Toll-like receptors, which
subsequently leads to the production of pro-inflammatory cytokines and chemokines from immune cells (neutrophils, macrophages, T-cells). If this cascade is triggered in (or
reaches) the uterus, cytokines (primarily IL-1) can act via their receptors to activate gestational tissue in preparation for labor. This activation is driven by a class of proteins
referred to as uterine activation proteins (UAPS; such as OXR, COX-2, MMPs, CX-43 . . . ). The induction of UAPs by inflammation increases myometrial contractility and drives
cervical ripening and the rupture of membranes, which promotes unscheduled labor onset. CRH, corticotrophin-releasing hormone; ET-1, endothelin-1.
40
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
change in the first extracellular loop of the receptor and further
facilitates the interaction of IL-1RI with the IL-1 receptor accessory
protein (IL-1RAcP), a transmembrane protein required for signal
transduction [50,51]. IL-1RAcP and IL-1RII also exist in soluble
form, and act mostly as decoys. Another isoform of IL-1RAcP was
recently discovered and referred to as IL-1RAcPb [52]. Although IL1RAcPb expression has been described to be restricted to neurons,
our group was able to amplify its mRNA from rat gestational tissues
(mostly uterus, but also cervix, ovaries and placenta) [53] and
human uterus (Olson DM, unpublished data).
2.4. IL-1Ra
IL-1 is a potent cytokine which is active at low concentrations;
1% of IL-1R1 occupancy is sufficient to induce maximum biological
response [54]. For this reason, IL-1 signaling is tightly regulated
through an endogenous inhibitor feedback system. IL-1Ra is an
endogenous inhibitor of IL-1a and IL-1b which acts by competitively binding to IL-1RI without activating it [55]. Two structural
variants have been identified: a secreted glycosylated form (sIL1Ra) and an intracellular form (icIL-1Ra) [39,56]. IL-1Ra is secreted
by most cell types including myeloid and lymphoid cells [57–61]. A
Fig. 2. Signaling pathways of the IL-1 system and available antagonists of the IL-1 receptor.
The IL-1 system is composed of IL-1RI and IL-1RAcP, which form a functional complex with IL-1 (a or b). This ligand–receptor complex signals via two canonical pathways: the
kinase pathway leading to the activation of transcription factor AP-1, and the NF-kB pathway. The nuclear translocation of these transcription factors promotes the
transcription of key pro-inflammatory, pro-labor genes including PGHS2,IL6, IL8 and CCL2. This system is tightly regulated by the endogenously-produced IL-1 inhibitors IL1Ra, sIL-1RAcP, IL-1RII (soluble and membrane-bound), and others (not shown). Three IL-1 receptor antagonists are currently available to counter IL-1 action: Anakinra,
Canakinumab and Rilonacept. Other available strategies to counter IL-1 action include CSAIDs and NF-kB inhibitors. MEKs, mitogen-activated protein kinase kinases.
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
41
Fig. 3. IL-1 b synthesis and maturation via the inflammasome in response to DAMPs and PAMPs.
The inflammasome is an active component of the innate immune response to infection and allows the maturation of IL-1b into its functional form. Signal 1, TLR agonists (e.g.,
PAMPs and DAMPs) promote pro-IL-1b transcriptional induction via transcription factors AP-1 and NF-kB; signal 2, NLR agonists (also include PAMPs and DAMPs) induce
inflammasome activation and IL-1b maturation. NLRP3; NOD-like receptor family, pyrin domain containing 3.
100 fold or greater excess in IL-1Ra over IL-1 is required to prevent
IL-1R1 activation [62]. Altogether, IL-1Ra, the soluble form of IL1RAcP (sIL-1RAcP), the membrane-bound and secreted IL-1 receptor II (sIL-1RII), and the soluble naturally occurring “shed” domains
of each of the extracellular IL-1R chains, help to dampen IL1 effects and therefore represent endogenous inducible antiinflammatory mechanisms [63,64].
2.5. Canonical pathway
IL-1R1/IL-1RAcP complex possesses conserved intracellular
regions, the Toll- and IL-1R–like (TIR) domains [65], which
mediate the protein-protein interaction of two signaling proteins,
myeloid differentiation primary response gene 88 (MYD88) and
interleukin-1 receptor–activated protein kinase (IRAK) 4 [66,67].
Knock-out mice for either MYD88 or IRAK4 have dysfunctional IL-1
signaling [68]. IRAK4 can phosphorylate itself, which allows it to
phosphorylate IRAK1 and IRAK2. Subsequently, tumor necrosis
factor receptor–associated factor (TRAF) 6 is recruited [69,70].
Downstream cascades activated by TRAF6 eventually lead to the
nuclear translocation of the transcription factor nuclear factorkappa B (NF-kB) [71,72] and to the phosphorylation of mitogenactivated protein kinase (MAPK) p38 and stress-activated protein
kinase (SAPK) JNK, which in turn leads to the activation of proteins
that form transcription factor activator protein-1 (AP-1) [73]. NFkB and AP-1 are jointly involved in the expression of numerous
pro-inflammatory genes including: PGHS2 [74], IL6 [75], IL8 [76]
and CCL2 [77] (refer to Fig. 2). NF-kB [78,79] and more recently AP1 [80,81] have been associated with PTB, and inhibition of either
NF-kB (Nadeau-Vallée and Chemtob, unpublished) or AP-1 [82]
with selective inhibitors is sufficient to reduce IL-1-induced PTB in
mice. Hence, the role of IL-1 in the onset of parturition is mainly
mediated by NF-kB and AP-1 through specific transcription of
target genes implicated in inflammation.
3. Role of interleukin-1 in preterm labor
IL-1 was the first cytokine to be implicated in the mechanism of
PTB associated with infection or acute inflammation as well as
spontaneous delivery at term in humans [31,32]. Evidence that IL1 plays a role in physiological and pathological labor of humans
comprise the following: (1) human parturition has been associated
with increased levels of IL-1b in the cervix, the myometrium and in
fetal membranes [25], regardless of the presence of infection [83];
(2) IL-1b concentration and bioactivity increases in AF of women
with PTL and infection [32], and seems to be associated with PTB
[84]; (3) elevated maternal plasma levels of IL-1b are associated
with PTL [85]; (4) IL-1b is produced in response to bacterial
endotoxins in ex vivo gestational tissues [86,87]; and (5) IL-1b
stimulation of human uterine-derived cells induces UAP genes
[82,88,89]. In particular, IL-1b was demonstrated to induce the
expression of prostaglandin H synthase 2 (PGHS-2, also named
COX-2), an enzyme catalyzing the synthesis of prostaglandins (e.g.,
PGE2, PGF2a) from arachidonic acid, in human gestational tissues
[90–94]. These prostaglandins are known to induce cervical
ripening [95,96] and myometrial contractions [97,98].
Animal studies support human data and further provide more
insight into the mechanism of action of IL-1 in gestational tissues
during labor. The main findings obtained with animals include: (1)
IL-1b induces PTB in multiple animal models including mouse
[33,99,100], rabbit [101] and nonhuman primate [34] when
administrated through the systemic, intra-uterine or intraamniotic route; (2) preterm delivery after lipopolysaccharide
administration is preceded by the appearance of dramatic
increases in maternal serum and AF concentrations of IL-1a
[102]; (3) antagonism of IL-1 receptor (using small peptidomimetics) decreases endotoxin-induced PTB in mice [82]; (4)
administration of IL-1b prematurely activates the uterus in mice
and increases myometrial contractility [82]; and (5) IL-1b activates
42
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
Rho/ROCK pathway in mouse myometrial smooth muscle cells
which contributes to cytoskeleton remodelling and contractility,
and antagonism of IL-1 receptor prevents this process [82].
Collectively, the evidence presented underscores the importance
of IL-1 in (human and animal) labor.
1b promotes ex vivo myometrium contractility in mice, which is
abolished upon co-treatment with a selective IL-1 receptor
antagonist [82].
3.1. IL-1 in preterm labor associated with infection
The genes coding for IL-1b (IL1B) and IL-1Ra (IL1RN) are both
located adjacent to each other on chromosome 2. Different alleles
in intron 2 of IL1RN are associated with varying levels of IL-1b and
IL-1Ra [121,122]. Expression by the fetus of the IL1RN *2 allele was
associated with enhanced mid-trimester intra-amniotic IL-1b
production and high IL-1b/IL-1Ra ratio, and was associated with
increased risk for PTB (p < 0.0001) [36]. Also, fetal carriage of
IL1B + 3953*1 and IL1RN*2 alleles was associated with risk for PTB
in African and Hispanic populations [35]. Previous data suggest
that some polymorphisms in the fetal IL-1 system are likely to
predispose to PTB in case of an intra-amniotic pro-inflammatory
immune response [123].
Maternal carriage of at least one copy of IL1RN *2 is also
associated with increased risk to PTB [124,125]. Whereas IL1B +
3953C > T, a common IL1B polymorphism which has been shown to
elevate the capacity to produce IL1B in vitro [126], has yielded
controversial observations on the risk reduction for PTB [127].
While the rare allele for the IL1B promoter region (IL1B-31T > C)
was found to be associated with PTB [37].
Infection is implicated in approximatively 40% of PTB, and is
often subclinical. During infection, bacterial products are recognized by PRRs, which include scavenger receptors, TLRs, C-type
lectins and NOD-like receptors. Studies in mice found that TLRs are
essential mediators of bacterial stimuli leading to PTB [103–105].
Specifically, endotoxins from Gram-negative bacteria bind to TLR4, whereas exotoxins from Gram-positive bacteria bind to TLR-2
[106]. In humans, TLR-2 and TLR-4 are found in the cervix,
endometrium and fallopian tubes [107], in the placenta [108] and
in other cells at the fetal–maternal interface [18], and are upregulated in cases of chorioamnionitis and during parturition
[109].
The pathophysiology of PTL in presence of infection has been
attributed to the release of pro-inflammatory cytokines, principally IL-1 [110]. The activation of TLRs leads to induction of
downstream inflammatory cascade (including NF-kB activation),
which promotes cytokine production. Accordingly, the TLR4 ligand
lipopolysaccharide has been shown to induce IL-1 production ex
vivo on human gestational tissues [86,87]. In human pregnancies,
IL-1 is produced in the decidua and its levels increase in presence of
microorganisms and bacterial products [102,111]. Also, in pregnant
women with infection, increased concentration and bioactivity of
IL-1 is observed in AF [32,112]. Interestingly, a disproportionate
increase in the IL-1b/IL-1Ra ratio in response to Gram-negative
infection has been found to correlate with PTB [113].
Germinal cell knockout mice deficient in IL-1 receptor or IL-1b
are not protected against endotoxin-induced PTB, likely because of
compensatory mechanisms; however, these animals do exhibit
lower inflammatory responses to endotoxins [114,115]. Moreover,
mice lacking both IL-1 receptor and TNF receptor are protected
against endotoxin-induced PTB [116], suggesting a complementary
role of those cytokines that would be altogether essential. On the
other hand, treatment with both IL-1Ra and TNF receptor
antagonists did not prevent endotoxin-induced PTB [117]; this
discrepancy between genetic and pharmacological approaches
may be due to doses and nature of antagonists utilized. In an
extensive study conducted by our group we have shown that IL-1 is
a central player in PTB [82] and placental defects [118] induced by
bacterial endotoxins. Specifically, we found that a systemic
injection of LPS or lipoteichoic acid (LTA; a TLR2 ligand), which
respectively mimic Gram and Gram+ infection, induced numerous
pro-inflammatory and pro-labor genes in the uterus (such as IL1B,
IL6, CCL2, GJA1, OXTR, PTGFR and PGHS2), and was followed by PTB;
transcription of these genes and PTB was significantly decreased
upon co-treatment with a small peptidomimetic noncompetitive
IL-1 receptor antagonist. Together, the data available to date
suggest that IL-1 exhibits a significant role in (murine) infectioninduced PTB, and its effects can be antagonized pharmacologically.
3.2. Myometrial cells excitability
In cultured human myometrial smooth muscle cells, IL-1b was
found to enhance cell excitability and basal calcium entry,
suggesting a role in the activation of uterine contractility through
modulation of calcium signaling [119]. IL-1b also induced an upregulation of transient receptor potential canonical (TRP)-3, a
putative calcium entry channel implicated in labor, in human
myometrium [120]. Correspondingly, we have also shown that IL-
3.3. Polymorphisms in IL-1-related genes and PTB
3.4. Prediction of PTB with levels of IL-1 or IL-1Ra in tissues and fluids
It has been abundantly suggested that IL-1 can be a promising
potential predictor of PTB for two main reasons: (1) its levels in AF
are elevated in mid-trimester and positively associated with
preterm birth [84] and microbial penetration of the amnion [112];
(2) mRNA levels of IL-1b are elevated in the human cervix during
PTL [128]. Several studies have correlated PTB with levels of IL-1b
in human cervicovaginal fluids [129], in AF [84] and in premature
neonate blood [38]. Moreover, measurements of IL-1Ra levels in
maternal blood [130] and in cervicovaginal fluids [30] of women in
mid-term gestation was able to accurately predict PTB and was
associated with increased rate of PTL [131]. Since IL-1Ra counterbalances the pro-inflammatory action of IL-1b, the IL-1b/IL-1Ra
ratio is important in the initiation of the inflammatory cascade that
leads to the onset of labor. Interestingly, in cervicovaginal fluid, IL1Ra levels decrease as labor approaches, while IL-1b rises,
indicating a pro-inflammatory shift in the IL-1b/IL-1Ra balance
[132]. Accordingly, the IL-1b/IL-1Ra ratio was significantly higher
in decidual samples of women with spontaneous labor compared
to women without labor, as the increase of IL-1b in the decidua
turned out to be the major cause of the ratio change [39]. Of
interest, data from our group show that IL-1a and IL-1b
concentration are also significantly higher in placenta from
pregnancies at high risk of PTB in association with placental
dysfunction [133], which may be of interest for the identification of
biomarkers of placental dysfunction and PTB.
3.5. Implication of IL-1 in hormonal regulation related to parturition
Progesterone is implicated in human pregnancy maintenance
by promoting uterine quiescence and in most species, progesterone withdrawal induces labor [134]. IL-1b has been shown to
facilitate the conversion of progesterone to the inactive metabolite
20a-hydroxyprogesterone in human cervical fibroblasts [135].
Interestingly, IL-1b was also shown to inhibit progesterone
production by primate luteal cells in vitro [136]. This suggests
that IL-1 may contribute to the activation of the uterus by
inhibiting progesterone activity.
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
Corticotrophin-releasing hormone (CRH) is a peptide hormone
part of the HPA axis which leads to cortisol production from the
adrenal cortex in response to stress. CRH plays an important role
in coordinating and regulating the physiologic conditions of
parturition [137–139] and appears to be an important mediator of
PTB associated with stress [140,141]. Since IL-1 is central to many
pro-labor pathways, its possible role in modulating CRH has been
explored. IL-1b was found to induce CRH expression in human
placenta [142] and its receptor CRH-R1 in human myometrium
[143]. Along these lines, suggestions have also been made that
IL-1b could act as a positive effector on placental CRH release
in humans [85]. Moreover, IL-1b has been shown to inhibit
placental 11 beta-hydroxysteroid dehydrogenase type 2, an
enzyme responsible for the inactivation of cortisol, in human
placental villi explants [144]. These studies suggest that IL-1b
might play a role in the induction of CRH and its receptor and in
the reduction of cortisol metabolism in intrauterine tissues.
A role for IL-1 in the regulation of other hormones implicated in
labor have also been suggested as it applies to oxytocin [145],
endothelin-1 [89,146] and estrogen [147].
43
decrease in IL-1Ra, which is significantly correlated with labor
onset [132].
Interestingly, a study in mice has uncovered a signal of parturition
arising from fetal lungs, which in turn induces the production of IL1 at term. Surfactant protein A (SP-A) concentration in AF rises near
term and is associated with increased IL-1b and NF-kB expression in
AF-resident macrophages, increased macrophage migration to the
maternal uterus, and increased levels of IL-1 in uterine tissues, which
is thought to herald labor [154]. However the complexity of labor is
highlighted by the fact that germline knockout mice with a disrupted
IL-1 system (IL-1b null mice [155], IL-1b converting enzyme null
mice [156], and IL-1 receptor type 1 null mice [157]) are fully fertile
and deliver at term [158], suggesting that mechanisms other than IL1 ensure birth at term.
5. Therapies available to counter interleukin-1 action
Available pharmacological strategies to antagonize the action of
IL-1 include: IL-1 receptor competitive antagonists, non-specific
NF-kB inhibitors and cytokine suppressive anti-inflammatory
drugs (CSAIDs) (see Fig. 2).
3.6. Modulation of other factors implicated with labor
5.1. IL-1 competitive antagonists
In a genome-wide expression profiling study using human
myometrial PHM1-31 cells in response to IL-1b, Chevillard et al.
identified enhanced expression of many genes implicated in labor
including cell adhesion factors (such as VCAM1 and ICAM1),
angiogenesis modulators and several extracellular matrix (ECM)
remodeling enzymes (including TNC and PLAU) [89]. Another study
from a different group found that IL-1b up-regulated ECM
remodelling enzymes, precisely matrix metalloproteinases
(MMPs) in human uterine cells [148], while it down-regulated
the expression of tissue inhibitor of metalloproteinase (TIMP)-2 in
the human cervix [149], which further promotes MMPs accumulation; MMPs contribute to cervical ripening during labor [150].
Vascular-endothelial growth factor (VEGF) is important for
growth and maintenance of the decidua. The expression of VEGF
mRNA is significantly increased in the chorio-decidua from women
undergoing spontaneous PTL compared to those going into
spontaneous term labor [151]. Interestingly, the expression of
VEGF is increased in vitro in human decidual stromal cells
stimulated with IL-1b [152].
In a recent study monitoring the global inflammatory
transcriptional profile in human term decidual cells, treatment
with IL-1b elicited a regulation of 428 transcripts of mRNA
(including cytokines, chemokines and other inflammatory mediators genes) and micro RNA [153], highlighting the vast scope of its
effect in gestational tissue.
4. IL-1 in normal term labor
As previously mentioned, term and preterm labor share
similarities, and most of the major players in PTL are also
implicated in term labor. The onset of labor is a complex process
independently of the timing of delivery and is less likely to be
caused by a single trigger; rather labor is the result of an interaction
of various contributors. In this context, IL-1 has been suggested to
exert an important contribution towards the onset of labor at term
mainly because of its role in the induction of prostaglandin
production by intrauterine tissues [32]. Term delivery without
infection is associated with a rise of IL-1b mRNA expression in
decidua and placenta [39] in addition to an increase in the levels of
IL-1b in the amniotic [31] and cervicovaginal [129] fluids. IL-1a
(and IL-1b) concentrations also increase in cervicovaginal fluid
within 2 weeks prior to term labor, and are associated with a
Three IL-1 targeting agents are approved for clinical use to this
day: the IL-1 antagonist anakinra (Kineret), the soluble decoy
receptor rilonacept (Arcalyst) and the neutralizing monoclonal antiIL-1b antibody canakinumab (Ilaris). These pharmacological agents
are FDA-approved for Cryopyrin-Associated Periodic Syndromes
(CAPS) and rheumatoid arthritis (only Kineret), but are also being
considered for other inflammatory diseases such as gout and type2 diabetes [41,159]. None of these IL-1 blocking therapies are
approved for clinical use during pregnancy or for PTB prevention. All
three agents antagonize IL-1 action in a competitive manner by
preventing the binding of IL-1 to its receptor and therefore blocking
all downstream signal transduction, including NF-kB activation.
Reluctance to using these IL-1-targeting therapies in PTB include: (1)
large size and immunogenicity; (2) high costs; (3) limited efficacy to
prevent infection-induced PTB in pre-clinical studies [100,117,160];
(4) undesirable (long) half-life of Rilonacept and Canakinumab
(>3 weeks) for acute/sub-acute treatment of women in labor; (5)
inhibition of NF-kB which conveys important physiological roles
including cytoprotection and antioxidant response; and (6) hindrance in immune-surveillance. The latter can subject the fetus and
the mother at risk of infections [161,162], and could compound on the
relative state of immunosuppression established by pregnancy
[163–165]. In addition, since IL-1 has a role in the physiological
process of labor, total inhibition of IL-1 signaling per se could
influence the normal parturition process. For these reasons,
optimization of the pharmacological and biochemical properties
of those IL-1 receptor antagonists is desirable before they are used
as preventive therapeutics for PTB.
5.2. Non-specific NF-kB inhibitors
Since IL-1 signals in part via NF-kB, NF-kB inhibitors (most
studied are sulfasalazine and the anti-oxidant N-acetyl cysteine
[NAC]) can partly counter IL-1 action. However, despite its clear
contribution to the pathophysiology of PTL [78], NF-kB also
conveys important physiological roles. Some studies using NF-kB
inhibitors show efficacy to prevent inflammation, but also describe
adverse effects of the compounds. A recent study using sulfasalazine to inhibit NF-kB pointed out pro-apoptotic effects on ex vivo
human fetal membranes, despite strong efficacy in decreasing
inflammation [166]. It was then suggested that a complete
blockade of NF-kB activity would be undesirable in pregnancy
44
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
[79]. In a placebo-controlled randomized clinical trial of pregnant
women treated for bacterial vaginosis, NAC was shown to
significantly decrease PTB rates and neonatal mortality/morbidity
[167]. However, it should be pointed out that NAC is a non-specific
NF-kB inhibitor; its known effects also include inhibition of JNK,
p38 and AP-1; NAC acts mostly as an anti-oxidant [168].
Nonetheless, NAC may appear to exhibit potential promise for
prevention of PTB. Tyrphostins (tyrosine kinases inhibitors) exhibit
effects including NF-kB inhibition, and our group has shown their
efficacy to reduce murine LPS-induced PTB [169].
5.3. Cytokine suppressive anti-inflammatory drugs (CSAIDs)
This new class of drugs inhibits cytokine-mediated events, and
have been reviewed in [170]. These drugs include MAPK/SAPK and
NF-kB inhibitors. They have been FDA-approved for cancer, but are
not selective. MAPK inhibitors (e.g., Trametinib, Dabrafenib) and
SAPK JNK inhibitors (e.g., Sorafenib) inhibit partly IL-1 signaling
without affecting NF-kB. However, caution is advised since these
kinases are also involved in placental growth and differenciation
[171,172]. Likewise, FDA-unapproved selective NF-kB inhibitors (e.
g., TPCA-1, parthenolide and SC-514 [selective IKK complex
inhibitors]) may seem promising to prevent PTB but interfere
with desirable properties of NF-kB activation, specifically immune-surveillance and cytoprotection; FDA-approved NF-kB
inhibitors (e.g., Sunitinib, Lestaurtinib) lack selectivity to the
pathway [173] and thus undesirably increase off-target effects.
6. Inhibition of specific interleukin-1 signals using functional
selectivity
Over the past few years, a new class of pharmacological agents
has been described which exhibits functional selectivity. Allosteric modulators display functional selectivity by modulating
differently signaling pathways triggered by the binding of a
natural ligand on a receptor, inhibiting some signals and/or
enhancing others. Functional selectivity provides concrete
solutions to the different issues that competitive IL-1-targeting
therapies bear and therefore represents a promising option for
the development of IL-1 targeting therapies for the prevention of
PTL. For example, it provides a solution to avoid NF-kB inhibition
while inhibiting other IL-1-related pathways implicated in the
labor-associated inflammatory response, such as MAPK p38 and
SAPK JNK. Circumventing NF-kB inhibition may be safer
considering the concerns mentioned above. For example 101.10,
a noncompetitive biased ligand of IL-1 receptor developed by our
group reduced (more effectively than anakinra) IL-1-, TLR2- and
TLR4-induced PTB in mice without inhibiting NF-kB [82] (Fig. 4).
Despite being NF-kB-independent, 101.10 was more effective than
Kineret at decreasing numerous pro-inflammatory and pro-labor
genes in murine myometrium and placenta, and at decreasing
inflammation- and infection-induced premature activation of the
uterus and myometrial contractility at preterm. Another allosteric
modulator, PDC31, showed functional selectivity toward selective
prostaglandin F2a-mediated pathways and was efficient to safely
prevent PTB in mice [174]; PDC31 has now successfully completed
Phase 1b human clinical trial, and reveals safety and efficacy in
diminishing myometrial contractions [175].
6.1. Advantages of small noncompetitive peptides over large
competitive molecules
Small peptidomimetics (<12 amino acids) can be derived from
the sequence of specific regions of a receptor (or enzyme) and
thereby interfere with its activity, as amply documented [176–178].
Because these molecules interact with regions remote from the
natural orthosteric binding site, they exhibit allosteric properties
such as a noncompetitive mode of action and therefore are likely to
exert functional selectivity [179]. This results in multiple benefits
for small allosteric modulators over large competitive molecules,
which include: (1) Allosteric modulators have increased selectivity
over competitive drugs since their target is more specific; i.e., they
target a specific receptor-induced signal instead of all receptorinduced signals. This pharmacological attribute also reflects
greater specificity by only modulating the induction of specific
genes/proteins induced by ligand-mediated receptor activation,
which allows for example to alleviate an inflammatory response
with minimal hindrance on immuno-surveillance. (2) Due to
increased specificity, allosteric modulators are likely to be
deprived of major adverse effects. (3) Relative to protein-based
drugs, small peptidomimetics are smaller in size and therefore
have negligible immunogenicity and increased bioavailability,
including enteral bioavailability without any formulation [13]. (4)
These compounds exert high potency and high therapeutic index.
(5) Small peptides are not metabolized by (polymorphic) cytochrome P450, and hence are not subject to variable population
kinetics, and (6) peptidomimetics may also have the benefit of
being less expensive to produce than antibodies and biological
compounds. The latter is of particular interest considering the
epidemiologic disparity between countries regarding PTB. In high
income countries, almost 95% of babies born between 28 and
32 weeks of gestation survive, with more than 90% surviving
without impairment. In contrast, in many low-middle income
countries, only 30% of those born between 28 and 32 weeks of
gestation survive, with almost all those born at less than 28 weeks
dying in the first few days of life [180].
6.2. Drawbacks for the development of preventive therapies in PTB
Drugs targeting downstream events in the cascade leading to
PTB (e.g., tocolytics) have been widely used and all of them have
shown poor efficacy to prolonging gestation and to improve
neonatal outcome [181]. It has often been suggested that such
drugs are administrated too late to prevent delivery. On the other
hand, drugs targeting upstream/midstream events (e.g., aforementioned anti-inflammatory drugs) show promise to prolong
gestation, but their development in clinical trials is curbed by the
lack of tools for the early diagnosis of women at risks. PTB is
difficult to predict because no clinical criteria exist for early
diagnosis, which is inconvenient for the design of a randomized
clinical trial, (because there is no discriminator for enrolling
women) and for the determination of the timing of the treatment.
As of now, the only approved drug for the prevention of PTB is
Makena (hydroxyprogesterone caproate), and it is only administrated to women with a history of preterm delivery (approximatively 12% of those at risk). Hence, preventive antiinflammatory/anti-labor drugs (such as IL-1-targeting drugs)
and the development of diagnostic tools for the identification of
women at risk need to be jointly conducted as they are mutually
inclusive.
7. Implications for technology commercialization and
translation into clinical application—an unavoidable to prevent
PTB
In June 2014 The Lancet identified better prediction and
treatment as the top research priority for preterm birth in a
United Kingdom poll [182]. This commentary illustrates sadly that
in spite of good intentions, after 70 years of awareness of the
problem [183], health care providers, administrators, scientists
and pharmaceutical companies have been unable to develop
effective means to detect and delay PTB [184]. In large part this is
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
45
Fig. 4. Three distinct pharmacological strategies to inhibit IL-1 signals and their possible effects on other important systems.
Simplified representation of the interaction of different IL-1 modulators with three major components of the human immune response: the IL-1, TNFa and TLR systems. A
therapy that would provide minimal hindrance of these systems is more likely to benefit from less adverse effects, notably in immuno-surveillance. IL-1-specific inhibitors
(depicted in red) affect all signaling pathways that are downstream of IL-1 receptor activation (e.g., IL-1-induced AP-1 and NF-kB). Signal-specific inhibitors (depicted in
green) affect a single signal without specificity for the receptor triggering it (depicted are tumor necrosis factor receptor 1 [TNFR1] activated by TNFa and TLRs activated by
endotoxins). Whereas agents that exhibit functional selectivity (depicted in blue) affect specific IL-1 signals (e.g., IL-1-induced AP-1 or NF-kB), providing an unparalleled
advantage in specificity.
due to an incomplete understanding of the causes, pathways and
mechanisms of this complex disease, in part because of the fixation
upon stopping myometrial contractions, which is probably too late
to be very effective if targeted alone. Moreover, investment into the
basic science to understand PTB has been inadequate, likely due to
weak advocacy until recent years, which has led to an avoidance by
investors and large pharmaceutical companies to invest into the
development and commercialization of intellectual property that
could be translated into diagnosis and treatments.
Throughout this review, we have highlighted the central role of
IL-1b in the preterm birth cascade of events. Now a key antagonist
to the IL-1b action, 101.10, offers potential to delay PTB and to
protect the fetus against infection and inflammatory insult. The
heptapeptide, 101.10 [185], antagonizes the IL-1b receptor
complex blocking LPS, LTA and IL-1b-induced preterm birth in
mice [82]. This anti-inflammatory agent has also been used
effectively to block LTA-induced decreases in microvascular
density in the brains of newborn mice, which suggests it could
protect the human fetus against infection due to chorioamnionitis,
as described above. There are many advantages to these small
peptide allosteric receptor antagonists in that they appear to be
safe for mother and fetus, are not expensive or difficult to produce,
have excellent bioavailability, and are highly effective.
In addition to the development of new therapeutics, there have
been several recent advances in technologies to estimate risk for
preterm birth and to ascertain who should be treated. These
advances are essential for staging effective clinical trials of
promising therapeutics with minimal expense.
One of the most significant problem in women’s pregnancy
health is the absence of industry ready to support commercial
46
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
Table 1
Population/market potential for diagnostics with negative and positive predictive values.
Condition
# Subjects
Market penetration
s Cost/test
Total euros
fFN (NPV)
Other (PPV and NPV)
Symptomatic NA-EU-J
Symptomatic major markets
Previous PTBb
Routine 2nd trimester
Total s
2.27 Ma
9.89 Ma
1.78 M
59.43 M
35%
35%
50%
50%
180
180
100 5
100
143M
623M
445M
5.943B
s7.01
Yes
Yes
No
No
s623m
Yes
Yes
Yes
Yes
s7.01B
Major Markets include Australia, China, India, Mexico, and Russia in addition to North America (NA), the European Union (EU) and Japan (J).
fFN – fetal fibronectin test; Other – a test with both a high positive predictive value (PPV) and a high negative predictive value (NPV).
a
Total PTBs – spontaneous (50%)/30% (number who present with symptoms).
b
Estimate 3% of current pregnant population has had a previous preterm delivery (PTD).
development of safe and effective diagnostics and therapeutics to
assess early and treat women at risk of PTB. This derives, in part,
from a lack of awareness of the size of the international market for
diagnostics and therapeutics, fear of an adverse outcome for
treating two patients with potential consequent litigation or
negative effect upon sales or reputation of other company
products, the perceived high cost of clinical trials and knowing
who to treat (because some trials will be in asymptomatic women),
and the lack of investors willing to support Phases 1 and 2 testing.
Hence, new diagnostic tests with high positive predictive values
could ‘de-risk’ the investment into clinical trials by identifying the
women who should be enrolled and possibly monitoring the
effectiveness of the therapeutic.
To illustrate the potential population/market size for a new
diagnostic, we explored how a diagnostic with a high positive
predictive value enlarges the market potential for products.
Table 1 describes the population/market potential for diagnostics
with a high negative predictive value, but low positive predictive
values, such as Hologic’s Fetal Fibronectin (fFN) test,1 and one that
has both a high positive and negative predictive value, such as the
LMA.
At present the fFN and the Actim-Partum (another test with a
high negative predictive value) [189] tests are available in North
America, the European Union and Japan where they are
principally used in symptomatic women (those with signs of
preterm labor including uterine contractions, cervical dilatation
and/or preterm premature rupture of membranes). Only 10–20%
of these women will deliver early; the remainder will deliver at
term. The diagnostic tests with a negative predictive value are
quite good at indicating who will not deliver in 10 days and
therefore sent home. In these cases, the market potential is about
s143 million, assuming 35% market penetration and costs of
s180 per test. If the market size is increased to include all the
major markets, the gross sales increase to s623 million. In
contrast, a test that has a high negative plus a high positive
predictive value can be used in these situations plus several
others such as assessing risk for delivering women who have had
a previous preterm delivery, where the risk is 15–33%. The
frequency of testing in this market (at least 5 times during a
pregnancy) would likely drive the per-test cost down to
s100 each, which would drive up the market penetration to
50% with a global sales potential of s445. The largest market,
though, for a test with a positive predictive value would be a
routine second trimester examination at the age of viability
(22 weeks) of the fetus. This market is estimated at s5.9 billion.
Summing together, the total worldwide market for all indications
would be s7.1 billion for a combined positive and negative
1
Recent quantitative evaluation of fFN alone or in conjunction with cervical
length improves its positive predictive value [186–188].
predictor. This is 10 times more than for a diagnostic that is only a
negative predictor of risk.
When examining the potential targeted population for a
therapeutic intervention in women diagnosed with preterm labor
using current medical evaluation procedures, it is estimated that
11.9 million patients will be identified in the same major
population as Table 1, or twice the number who will actually
deliver preterm. Various medical considerations will reduce to 45%
those in which prolongation of gestation is desirable. Of these,
about 71% will be late preterm and 29% early preterm. Of the
former, 35% will be treated, and 50% in the early preterm group will
be treated. A single course of treatment, priced at an estimated
s1500 (based on current therapeutic pricing), would yield a global
market potential of s3.14 billion.
This global target population potential could be expanded
several-fold when a good diagnostic is married to a good
therapeutic. Current medical evaluation of preterm labor means
overt display of preterm birth symptoms of women in labor. This is
really too late for effective intervention. Hence, combining an
effective diagnostic that predicts risk before symptoms appear
would achieve several benefits. First, it will identify those at risk
who may not have been characterized using other assessment tools
thereby targeting more women earlier in their pregnancies.
Second, it will reduce the number of women treated unnecessarily.
This will lead to starting treatments earlier, before symptoms and
labor begins, with better effectiveness and possibly with more
courses of treatment. From a global perspective, more women in
more populations may be diagnosed and treated; and from a health
standpoint, better pregnancy outcomes will ensue. Hence combining a good diagnostic with a good therapeutic will increase the
global benefit for each.
New scientific advances have identified the earlier or upstream
steps in the preterm labor process, particularly the central role of
IL-1b, providing new means to assess risk and new therapeutic
targets. Efforts are underway to develop new diagnostics that have
both high positive and negative predictive values and combining
them with new, safe therapeutics. Using them in tandem will
‘de-risk’ (and incentivise) investment into clinical trials thereby
hastening their arrival for clinical use, vastly identifying the target
population, improving treatment efficacy (originally geared to
target population), decreasing global perinatal health care costs,
increasing global market size and thus providing an incentive for
needed pharmaceutical/biotech partners for this unmet medical
need. Translation and commercialization efforts may for the first
time improve considerably pregnancy outcomes and give more
newborns a better start to life everywhere.
In summary, although IL-1 is a major player partaking in the
pathological induction of PTB, currently approved IL-1-targeting
therapies have failed to show expected efficacy in pre-clinical
studies, likely because their mechanism of action inhibits all IL1 receptor-associated signals which promotes immunosuppression and other undesired effects. Alternative IL-1-targeting
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
therapies include CSAIDs, NF-kB inhibitors and allosteric modulators of IL-1 receptor. Future studies are needed to show their
efficacy in human PTB.
Acknowledgements
We thank Dr. Mélanie Sanchez for a thorough review of this
work. This study was funded by GAPPS (Global Alliance for the
Prevention of Prematurity and Stillbirth, an initiative of Seattle
Children’s) and the Canadian Institutes of Health Research (CIHR).
M.N.V. was supported by a scholarship from the Suzanne
Veronneau-Troutman Funds associated with the Department of
Ophthalmology of Université de Montréal, by the Vision Research
Network (RRSV), by a scholarship from Fonds de Recherche en
Santé du Québec (FRSQ) and by a scholarship from the CIHR. D.O.
was supported by La Société Québécoise d'Hypertension Artérielle
(SQHA). S.C. holds a Canada Research Chair (Vision Science), and
the Leopoldine Wolfe Chair in translational research in age-related
macular degeneration.
References
[1] L. Liu, H.L. Johnson, S. Cousens, J. Perin, S. Scott, J.E. Lawn, et al., Global,
regional, and national causes of child mortality: an updated systematic
analysis for 2010 with time trends since 2000, Lancet 379 (2012) 2151–2161.
[2] B.E. Hamilton, D.L. Hoyert, J.A. Martin, D.M. Strobino, B. Guyer, Annual
summary of vital statistics: 2010–2011, Pediatrics 131 (2013) 548–558.
[3] R.E. Behrman, A. Butler, Preterm Birth Causes, Consequences, and Prevention,
National Academies Press (US), Washington D.C, 2007.
[4] R. Parturition Smith, New Engl. J. Med. 356 (2007) 271–283.
[5] R. Romero, M. Mazor, H. Munoz, R. Gomez, M. Galasso, D.M. Sherer, The
preterm labor syndrome, Ann. N.Y. Acad. Sci. 734 (1994) 414–429.
[6] R. Romero, J. Espinoza, J.P. Kusanovic, F. Gotsch, S. Hassan, O. Erez, et al., The
preterm parturition syndrome, BJOG: Int. J. Obstet. Gynaecol. 113 (Suppl. 3)
(2006) 17–42.
[7] A. Parizek, M. Koucky, M. Duskova, Progesterone, inflammation and preterm
labor, J. Steroid Biochem. Mol. Biol. 139 (2014) 159–165.
[8] H.N. Simhan, S.N. Caritis, Prevention of preterm delivery, New Engl. J. Med.
357 (2007) 477–487.
[9] R. Romero, S.K. Dey, S.J. Fisher, Preterm labor: one syndrome, many causes,
Science (New York) 345 (2014) 760–765.
[10] S.F. Rinaldi, J.L. Hutchinson, A.G. Rossi, J.E. Norman, Anti-inflammatory
mediators as physiological and pharmacological regulators of parturition,
Exp. Rev. Clin. Immunol. 7 (2011) 675–696.
[11] J.L. Cook, M.C. Shallow, D.B. Zaragoza, K.I. Anderson, D.M. Olson, Mouse
placental prostaglandins are associated with uterine activation and the
timing of birth, Biol. Reprod. 68 (2003) 579–587.
[12] P. Arthur, M.J. Taggart, B. Zielnik, S. Wong, B.F. Mitchell, Relationship between
gene expression and function of uterotonic systems in the rat during
gestation, uterine activation and both term and preterm labour, J. Physiol.
586 (2008) 6063–6076.
[13] I. Christiaens, D.B. Zaragoza, L. Guilbert, S.A. Robertson, B.F. Mitchell, D.M.
Olson, Inflammatory processes in preterm and term parturition, J. Reprod.
Immunol. 79 (2008) 50–57.
[14] S.L. Hillier, S.S. Witkin, M.A. Krohn, D.H. Watts, N.B. Kiviat, D.A. Eschenbach,
The relationship of amniotic fluid cytokines and preterm delivery, amniotic
fluid infection, histologic chorioamnionitis, and chorioamnion infection,
Obstet. Gynecol. 81 (1993) 941–948.
[15] A. Steinborn, H. Gunes, S. Roddiger, E. Halberstadt, Elevated placental
cytokine release, a process associated with preterm labor in the absence of
intrauterine infection, Obstet. Gynecol. 88 (1996) 534–539.
[16] R. Gomez, R. Romero, S.S. Edwin, C. David, Pathogenesis of preterm labor and
preterm premature rupture of membranes associated with intraamniotic
infection, Infect. Dis. Clin. North Am. 11 (1997) 135–176.
[17] M. Mazor, B. Furman, A. Bashiri, Cytokines in preterm parturition, Gynecol.
Endocrinol. Off. J. Int. Soc. Gynecol. Endocrinol. 12 (1998) 421–427.
[18] K. Koga, G. Mor, Toll-like receptors at the maternal-fetal interface in normal
pregnancy and pregnancy disorders, Am. J. Reprod. Immunol. 63 (2010) 587–
600.
[19] N. Gomez-Lopez, L.J. Guilbert, D.M. Olson, Invasion of the leukocytes into the
fetal-maternal interface during pregnancy, J. Leukoc. Biol. 88 (2010) 625–633.
[20] B.H. Yoon, R. Romero, S.H. Yang, J.K. Jun, I.O. Kim, J.H. Choi, et al., Interleukin6 concentrations in umbilical cord plasma are elevated in neonates with
white matter lesions associated with periventricular leukomalacia, Am. J.
Obstet. Gynecol. 174 (1996) 1433–1440.
[21] S.M. Cox, M.L. Casey, P.C. MacDonald, Accumulation of interleukin-1beta and
interleukin-6 in amniotic fluid: a sequela of labour at term and preterm,
Hum. Reprod. Update 3 (1997) 517–527.
47
[22] O. Dammann, A. Leviton, Maternal intrauterine infection, cytokines, and
brain damage in the preterm newborn, Pediatr. Res. 42 (1997) 1–8.
[23] D.J. Dudley, Pre-term labor: an intra-uterine inflammatory response
syndrome? J. Reprod. Immunol. 36 (1997) 93–109.
[24] A.J. Thomson, J.F. Telfer, A. Young, S. Campbell, C.J. Stewart, I.T. Cameron, et al.,
Leukocytes infiltrate the myometrium during human parturition: further
evidence that labour is an inflammatory process, Hum. Reprod. 14 (1999)
229–236.
[25] I. Osman, A. Young, M.A. Ledingham, A.J. Thomson, F. Jordan, I.A. Greer, et al.,
Leukocyte density and pro-inflammatory cytokine expression in human fetal
membranes, decidua, cervix and myometrium before and during labour at
term, Mol. Hum. Reprod. 9 (2003) 41–45.
[26] M.A. Elovitz, C. Mrinalini, Animal models of preterm birth, Trends Endocrinol.
Metabol. TEM 15 (2004) 479–487.
[27] S. Hamilton, Y. Oomomian, G. Stephen, O. Shynlova, C.L. Tower, A. Garrod,
et al., Macrophages infiltrate the human and rat decidua during term and
preterm labor: evidence that decidual inflammation precedes labor, Biol.
Reprod. 86 (2012) 39.
[28] B. Jacobsson, I. Mattsby-Baltzer, B. Andersch, H. Bokstrom, R.M. Holst, N.
Nikolaitchouk, et al., Microbial invasion and cytokine response in amniotic
fluid in a Swedish population of women with preterm prelabor rupture of
membranes, Acta Obstet. Gynecol. Scand. 82 (2003) 423–431.
[29] A. Torbe, R. Czajka, A. Kordek, R. Rzepka, S. Kwiatkowski, J. Rudnicki, Maternal
serum proinflammatory cytokines in preterm labor with intact membranes:
neonatal outcome and histological associations, Eur. Cytokine Network 18
(2007) 102–107.
[30] S. Liong, M.K. Di Quinzio, G. Fleming, M. Permezel, G.E. Rice, H.M. Georgiou,
Prediction of spontaneous preterm labour in at-risk pregnant women,
Reproduction (Cambridge, England) 146 (2013) 335–345.
[31] R. Romero, S.T. Parvizi, E. Oyarzun, M. Mazor, Y.K. Wu, C. Avila, et al., Amniotic
fluid interleukin-1 in spontaneous labor at term, J. Reprod. Med. 35 (1990)
235–238.
[32] R. Romero, D.T. Brody, E. Oyarzun, M. Mazor, Y.K. Wu, J.C. Hobbins, et al.,
Infection and labor. III. Interleukin-1: a signal for the onset of parturition, Am.
J. Obstet. Gynecol. 160 (1989) 1117–1123.
[33] R. Romero, M. Mazor, B. Tartakovsky, Systemic administration of interleukin1 induces preterm parturition in mice, Am. J. Obstet. Gynecol. 165 (1991)
969–971.
[34] D.W. Sadowsky, K.M. Adams, M.G. Gravett, S.S. Witkin, M.J. Novy, Preterm
labor is induced by intraamniotic infusions of interleukin-1beta and tumor
necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a
nonhuman primate model, Am. J. Obstet. Gynecol. 195 (2006) 1578–1589.
[35] M.R. Genc, S. Gerber, M. Nesin, S.S. Witkin, Polymorphism in the interleukin1 gene complex and spontaneous preterm delivery, Am. J. Obstet. Gynecol.
187 (2002) 157–163.
[36] S.S. Witkin, S. Vardhana, M. Yih, K. Doh, A.M. Bongiovanni, S. Gerber,
Polymorphism in intron 2 of the fetal interleukin-1 receptor antagonist
genotype influences midtrimester amniotic fluid concentrations of
interleukin-1beta and interleukin-1 receptor antagonist and pregnancy
outcome, Am. J. Obstet. Gynecol. 189 (2003) 1413–1417.
[37] M.V. Hollegaard, J. Grove, P. Thorsen, X. Wang, S. Mandrup, M. Christiansen,
et al., Polymorphisms in the tumor necrosis factor alpha and interleukin 1beta promoters with possible gene regulatory functions increase the risk of
preterm birth, Acta Obstet. Gynecol. Scand. 87 (2008) 1285–1290.
[38] K. Skogstrand, D.M. Hougaard, D.E. Schendel, N.P. Bent, C. Svaerke, P. Thorsen,
Association of preterm birth with sustained postnatal inflammatory
response, Obstet. Gynecol. 111 (2008) 1118–1128.
[39] M. Ammala, T. Nyman, A. Salmi, E.M. Rutanen, The interleukin-1 system in
gestational tissues at term: effect of labour, Placenta 18 (1997) 717–723.
[40] C.A. Dinarello, Interleukin-1, Cytokine Growth Factor Rev. 8 (1997) 253–265.
[41] C.A. Dinarello, A. Simon, van, M. der, J.W. eer, Treating inflammation by
blocking interleukin-1 in a broad spectrum of diseases, Nat. Rev. Drug Discov.
11 (2012) 633–652.
[42] Y. Berda-Haddad, S. Robert, P. Salers, L. Zekraoui, C. Farnarier, C.A. Dinarello,
et al., Sterile inflammation of endothelial cell-derived apoptotic bodies is
mediated by interleukin-1alpha, Proc. Natl. Acad. Sci. U. S. A. 108 (2011)
20684–20689.
[43] C.A. Dinarello, Interleukin-1 in the pathogenesis and treatment of
inflammatory diseases, Blood 117 (2011) 3720–3732.
[44] C. Garlanda, C.A. Dinarello, A. Mantovani, The interleukin-1 family: back to
the future, Immunity 39 (2013) 1003–1018.
[45] J.E. Sims, R.B. Acres, C.E. Grubin, C.J. McMahan, J.M. Wignall, C.J. March, et al.,
Cloning the interleukin 1 receptor from human T cells, Proc. Natl. Acad. Sci. U.
S. A. 86 (1989) 8946–8950.
[46] S.K. Dower, E.E. Qwarnstrom, R.C. Page, R.A. Blanton, T.S. Kupper, E. Raines,
et al., Biology of the interleukin-1 receptor, J. Invest. Dermatol. 94 (1990) 68s–
73s.
[47] J.E. Sims, M.A. Gayle, J.L. Slack, M.R. Alderson, T.A. Bird, J.G. Giri, et al.,
Interleukin 1 signaling occurs exclusively via the type I receptor, Proc. Natl.
Acad. Sci. U. S. A. 90 (1993) 6155–6159.
[48] C.A. Dinarello, The many worlds of reducing interleukin-1, Arthr. Rheum. 52
(2005) 1960–1967.
[49] F. Colotta, F. Re, M. Muzio, R. Bertini, N. Polentarutti, M. Sironi, et al.,
Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4,
Science (New York) 261 (1993) 472–475.
48
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
[50] S.A. Greenfeder, P. Nunes, L. Kwee, M. Labow, R.A. Chizzonite, G. Ju, Molecular
cloning and characterization of a second subunit of the interleukin 1 receptor
complex, J. Biol. Chem. 270 (1995) 13757–13765.
[51] H. Wesche, C. Korherr, M. Kracht, W. Falk, K. Resch, M.U. Martin, The
interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1induced activation of interleukin-1 receptor-associated kinase (IRAK) and
stress-activated protein kinases (SAP kinases), J. Biol. Chem. 272 (1997)
7727–7731.
[52] D.E. Smith, B.P. Lipsky, C. Russell, R.R. Ketchem, J. Kirchner, K. Hensley, et al., A
central nervous system-restricted isoform of the interleukin-1 receptor
accessory protein modulates neuronal responses to interleukin-1, Immunity
30 (2009) 817–831.
[53] T.B.H. Ishiguro, J. Takeda, X. Fang, D.M. Olson, Interleukin (IL)-1 receptor I and
IL-1 receptor accessory protein increase at delivery in rat uterus, Reprod. Sci.
21 (2014) 238A.
[54] S.K. Dower, J.E. Sims, Molecular characterisation of cytokine receptors, Ann.
Rheum. Dis. 49 (Suppl. 1) (1990) 452–459.
[55] P. Seckinger, J.W. Lowenthal, K. Williamson, J.M. Dayer, H.R. MacDonald, A
urine inhibitor of interleukin 1 activity that blocks ligand binding, J.
Immunol. (Baltimore, Md: 1950) 139 (1987) 1546–1549.
[56] W.P. Arend, Interleukin 1 receptor antagonist. A new member of the
interleukin 1 family, J. Clin. Invest. 88 (1991) 1445–1451.
[57] P. Roux-Lombard, C. Modoux, J.M. Dayer, Production of interleukin-1 (IL-1)
and a specific IL-1 inhibitor during human monocyte-macrophage
differentiation: influence of GM-CSF, Cytokine 1 (1989) 45–51.
[58] D. Gruaz-Chatellard, C. Baumberger, J.H. Saurat, J.M. Dayer, Interleukin
1 receptor antagonist in human epidermis and cultured keratinocytes, FEBS
Lett. 294 (1991) 137–140.
[59] S.R. McColl, R. Paquin, C. Menard, A.D. Beaulieu, Human neutrophils produce
high levels of the interleukin 1 receptor antagonist in response to
granulocyte/macrophage colony-stimulating factor and tumor necrosis
factor alpha, J. Exp. Med. 176 (1992) 593–598.
[60] G. Palmer, P.A. Guerne, F. Mezin, M. Maret, J. Guicheux, M.B. Goldring, et al.,
Production of interleukin-1 receptor antagonist by human articular
chondrocytes, Arthr. Res. 4 (2002) 226–231.
[61] S. Perrier, B. Kherratia, C. Deschaumes, S. Ughetto, J.L. Kemeny, M. BaudetPommel, et al., IL-1ra and IL-1 production in human oral mucosal epithelial
cells in culture: differential modulation by TGF-beta1 and IL-4, Clin. Exp.
Immunol. 127 (2002) 53–59.
[62] W.P. Arend, Interleukin-1 receptor antagonist, Adv. Immunol. 54 (1993) 167–
227.
[63] W.P. Arend, G. Palmer, C. Gabay, IL-1, IL-18, and IL-33 families of cytokines,
Immunol. Rev. 223 (2008) 20–38.
[64] A. Weber, P. Wasiliew, M. Kracht, Interleukin-1 (IL-1) pathway, Sci. Signal. 3
(2010) cm1.
[65] J. Radons, S. Dove, D. Neumann, R. Altmann, A. Botzki, M.U. Martin, et al., The
interleukin 1 (IL-1) receptor accessory protein Toll/IL-1 receptor domain:
analysis of putative interaction sites in vitro mutagenesis and molecular
modeling, J. Biol. Chem. 278 (2003) 49145–49153.
[66] S. Li, A. Strelow, E.J. Fontana, H. Wesche, IRAK-4: a novel member of the IRAK
family with the properties of an IRAK-kinase, Proc. Natl. Acad. Sci. U. S. A. 99
(2002) 5567–5572.
[67] C. Brikos, R. Wait, S. Begum, L.A. O'Neill, J. Saklatvala, Mass spectrometric
analysis of the endogenous type I interleukin-1 (IL-1) receptor signaling
complex formed after IL-1 binding identifies IL-1RAcP, MyD88, and
IRAK-4 as the stable components, Mol. Cell. Proteom.: MCP 6 (2007)
1551–1559.
[68] N. Suzuki, S. Suzuki, G.S. Duncan, D.G. Millar, T. Wada, C. Mirtsos, et al., Severe
impairment of interleukin-1 and Toll-like receptor signalling in mice lacking
IRAK-4, Nature 416 (2002) 750–756.
[69] Z. Cao, J. Xiong, M. Takeuchi, T. Kurama, D.V. Goeddel, TRAF6 is a signal
transducer for interleukin-1, Nature 383 (1996) 443–446.
[70] T. Kawagoe, S. Sato, K. Matsushita, H. Kato, K. Matsui, Y. Kumagai, et al.,
Sequential control of Toll-like receptor-dependent responses by IRAK1 and
IRAK2, Nat. Immunol. 9 (2008) 684–691.
[71] Q. Huang, J. Yang, Y. Lin, C. Walker, J. Cheng, Z.G. Liu, et al., Differential
regulation of interleukin 1 receptor and Toll-like receptor signaling by
MEKK3, Nat. Immunol. 5 (2004) 98–103.
[72] J.H. Shim, C. Xiao, A.E. Paschal, S.T. Bailey, P. Rao, M.S. Hayden, et al., TAK1, but
not TAB1 or TAB2, plays an essential role in multiple signaling pathways in
vivo, Genes Dev. 19 (2005) 2668–2681.
[73] G. Cirillo, L. Casalino, D. Vallone, A. Caracciolo, C. De, D. esare, P. Verde, Role of
distinct mitogen-activated protein kinase pathways and cooperation
between Ets-2, ATF-2, and Jun family members in human urokinase-type
plasminogen activator gene induction by interleukin-1 and tetradecanoyl
phorbol acetate, Mol. Cell. Biol. 19 (1999) 6240–6252.
[74] V.C. Allport, D.M. Slater, R. Newton, P.R. Bennett, NF-kappaB and AP-1 are
required for cyclo-oxygenase 2 gene expression in amnion epithelial cell line
(WISH), Mol. Hum. Reprod. 6 (2000) 561–565.
[75] A. Beetz, R.U. Peter, T. Oppel, W. Kaffenberger, R.A. Rupec, M. Meyer, et al.,
NF-kappaB and AP-1 are responsible for inducibility of the IL-6 promoter
by ionizing radiation in HeLa cells, Int. J. Radiat. Biol. 76 (2000) 1443–1453.
[76] S. Khanjani, V. Terzidou, M.R. Johnson, P.R. Bennett, NFkappaB and AP-1
drive human myometrial IL8 expression, Mediat. Inflamm. 2012 (2012)
504952.
[77] X. Deng, M. Xu, C. Yuan, L. Yin, X. Chen, X. Zhou, et al., Transcriptional
regulation of increased CCL2 expression in pulmonary fibrosis involves
nuclear factor-kappaB and activator protein-1, Int. J. Biochem. Cell Biol. 45
(2013) 1366–1376.
[78] T.M. Lindstrom, P.R. Bennett, The role of nuclear factor kappa B in human
labour, Reproduction (Cambridge, England) 130 (2005) 569–581.
[79] V.J. Cookson, N.R. Chapman, NF-kappaB function in the human myometrium
during pregnancy and parturition, Histol. Histopathol. 25 (2010) 945–956.
[80] D.A. MacIntyre, Y.S. Lee, R. Migale, B.R. Herbert, S.N. Waddington, D. Peebles,
et al., Activator protein 1 is a key terminal mediator of inflammation-induced
preterm labor in mice, FASEB J. 28 (2014) 2358–2368.
[81] R. Lim, M. Lappas, Differential expression of AP-1 proteins in human
myometrium after spontaneous term labour onset, Eur. J. Obstet. Gynecol.
Reprod. Biol. 177 (2014) 100–105.
[82] M. Nadeau-Vallee, C. Quiniou, J. Palacios, X. Hou, A. Erfani, A. Madaan, et al.,
Novel noncompetitive IL-1 receptor-biased ligand prevents infection- and
inflammation-induced preterm birth, J. Immunol. (Baltimore, Md: 1950)
(2015) .
[83] C.L. Elliott, J.A. Loudon, N. Brown, D.M. Slater, P.R. Bennett, M.H. Sullivan, IL1beta and IL-8 in human fetal membranes: changes with gestational age,
labor, and culture conditions, Am. J. Reprod. Immunol. 46 (2001) 260–267.
[84] K. Puchner, C. Iavazzo, D. Gourgiotis, M. Boutsikou, S. Baka, D. Hassiakos, et al.,
Mid-trimester amniotic fluid interleukins (IL-1beta, IL-10 and IL-18) as
possible predictors of preterm delivery, In vivo (Athens, Greece) 25 (2011)
141–148.
[85] N. Vitoratos, G. Mastorakos, A. Kountouris, K. Papadias, G. Creatsas, Positive
association of serum interleukin-1beta and CRH levels in women with preterm labor, J. Endocrinol. Invest. 30 (2007) 35–40.
[86] K.P. Himes, D. Handley, T. Chu, B. Burke, K. Bunce, H.N. Simhan, et al.,
Comprehensive analysis of the transcriptional response of human
decidual cells to lipopolysaccharide stimulation, J. Reprod. Immunol. 93
(2012) 17–27.
[87] O. Pavlov, O. Pavlova, E. Ailamazyan, S. Selkov, Characterization of cytokine
production by human term placenta macrophages in vitro, Am. J. Reprod.
Immunol. 60 (2008) 556–567.
[88] D.B. Zaragoza, R.R. Wilson, B.F. Mitchell, D.M. Olson, The interleukin 1betainduced expression of human prostaglandin F2alpha receptor messenger
RNA in human myometrial-derived ULTR cells requires the transcription
factor, NFkappaB, Biol. Reprod. 75 (2006) 697–704.
[89] G. Chevillard, A. Derjuga, D. Devost, H.H. Zingg, V. Blank, Identification of
interleukin-1beta regulated genes in uterine smooth muscle cells,
Reproduction (Cambridge, England). 134 (2007) 811–822.
[90] R. Romero, S. Durum, C.A. Dinarello, E. Oyarzun, J.C. Hobbins, M.D. Mitchell,
Interleukin-1 stimulates prostaglandin biosynthesis by human amnion,
Prostaglandins 37 (1989) 13–22.
[91] B. Lyons-Giordano, M.A. Pratta, W. Galbraith, G.L. Davis, E.C. Arner,
Interleukin-1 differentially modulates chondrocyte expression of
cyclooxygenase-2 and phospholipase A2, Exp. Cell Res. 206 (1993) 58–62.
[92] N.L. Brown, S.A. Alvi, M.G. Elder, P.R. Bennett, M.H. Sullivan, A spontaneous
induction of fetal membrane prostaglandin production precedes clinical
labour, J. Endocrinol. 157 (1998) R1–R6.
[93] S.R. Bartlett, R. Sawdy, G.E. Mann, Induction of cyclooxygenase-2 expression
in human myometrial smooth muscle cells by interleukin-1beta:
involvement of p38 mitogen-activated protein kinase, J. Physiol. 520 (Pt 2)
(1999) 399–406.
[94] P.N. Rauk, J.P. Chiao, Interleukin-1 stimulates human uterine prostaglandin
production through induction of cyclooxygenase-2 expression, Am. J. Reprod.
Immunol. 43 (2000) 152–159.
[95] A. Calder, M.P.L. Embrey, etter, Prostaglandins and the unfavourable cervix,
Lancet 2 (1973) 1322–1323.
[96] U. Ulmsten, L. Wingerup, P. Belfrage, G. Ekman, N. Wiqvist, Intracervical
application of prostaglandin gel for induction of term labor, Obstet. Gynecol.
59 (1982) 336–339.
[97] M.D. Mitchell, A.P. Flint, A.C. Turnbull, Stimulation of uterine activity by
administration of prostaglandin F-2alpha during parturition in sheep, J.
Reprod. Fertil. 48 (1976) 189–190.
[98] J.K. Pollard, M.D. Mitchell, Intrauterine infection and the effects of
inflammatory mediators on prostaglandin production by myometrial cells
from pregnant women, Am. J. Obstet. Gynecol. 174 (1996) 682–686.
[99] R. Romero, B. Tartakovsky, The natural interleukin-1 receptor antagonist
prevents interleukin-1-induced preterm delivery in mice, Am. J. Obstet.
Gynecol. 167 (1992) 1041–1045.
[100] K. Yoshimura, E. Hirsch, Effect of stimulation and antagonism of interleukin1 signaling on preterm delivery in mice, J. Soc. Gynecol. Invest. 12 (2005)
533–538.
[101] K. Bry, M. Hallman, Transforming growth factor-beta 2 prevents preterm
delivery induced by interleukin-1 alpha and tumor necrosis factor-alpha in
the rabbit, Am. J. Obstet. Gynecol. 168 (1993) 1318–1322.
[102] P.L. Fidel Jr., R. Romero, N. Wolf, J. Cutright, M. Ramirez, H. Araneda, et al.,
Systemic and local cytokine profiles in endotoxin-induced preterm
parturition in mice, Am. J. Obstet. Gynecol. 170 (1994) 1467–1475.
[103] M.A. Elovitz, Z. Wang, E.K. Chien, D.F. Rychlik, M. Phillippe, A new model for
inflammation-induced preterm birth: the role of platelet-activating factor
and Toll-like receptor-4, Am. J. Pathol. 163 (2003) 2103–2111.
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
[104] H. Wang, E. Hirsch, Bacterially-induced preterm labor and regulation of
prostaglandin-metabolizing enzyme expression in mice: the role of toll-like
receptor 4, Biol. Reprod. 69 (2003) 1957–1963.
[105] V. Ilievski, S.J. Lu, E. Hirsch, Activation of toll-like receptors 2 or 3 and preterm
delivery in the mouse, Reprod. Sci. 14 (2007) 315–320.
[106] S. Akira, K. Takeda, T. Kaisho, Toll-like receptors: critical proteins linking
innate and acquired immunity, Nat. Immunol. 2 (2001) 675–680.
[107] A. Fazeli, C. Bruce, D.O. Anumba, Characterization of Toll-like receptors in the
female reproductive tract in humans, Hum. Reprod. 20 (2005) 1372–1378.
[108] U. Holmlund, G. Cebers, A.R. Dahlfors, B. Sandstedt, K. Bremme, E.S. Ekstrom,
et al., Expression and regulation of the pattern recognition receptors Toll-like
receptor-2 and Toll-like receptor-4 in the human placenta, Immunology 107
(2002) 145–151.
[109] Y.M. Kim, R. Romero, T. Chaiworapongsa, G.J. Kim, M.R. Kim, H. Kuivaniemi,
et al., Toll-like receptor-2 and -4 in the chorioamniotic membranes in
spontaneous labor at term and in preterm parturition that are associated
with chorioamnionitis, Am. J. Obstet. Gynecol. 191 (2004) 1346–1355.
[110] R. Romero, M. Mazor, Y.K. Wu, M. Sirtori, E. Oyarzun, M.D. Mitchell, et al.,
Infection in the pathogenesis of preterm labor, Sem. Perinatol. 12 (1988)
262–279.
[111] R. Romero, Y.K. Wu, D.T. Brody, E. Oyarzun, G.W. Duff, S.K. Durum, Human
decidua: a source of interleukin-1, Obstet. Gynecol. 73 (1989) 31–34.
[112] C. Marconi, B.R. de Andrade Ramos, J.C. Peracoli, G.G. Donders, M.G. da Silva,
Amniotic fluid interleukin-1 beta and interleukin-6, but not interleukin8 correlate with microbial invasion of the amniotic cavity in preterm labor,
Am. J. Reprod. Immunol. 65 (2011) 549–556.
[113] M.R. Genc, S.S. Witkin, M.L. Delaney, L.R. Paraskevas, R.E. Tuomala, E.R.
Norwitz, et al., A disproportionate increase in IL-1beta over IL-1ra in
the cervicovaginal secretions of pregnant women with altered vaginal
microflora correlates with preterm birth, Am. J. Obstet. Gynecol. 190 (2004)
1191–1197.
[114] L.L. Reznikov, G. Fantuzzi, C.H. Selzman, B.D. Shames, H.A. Barton, H. Bell,
et al., Utilization of endoscopic inoculation in a mouse model of intrauterine
infection-induced preterm birth: role of interleukin 1beta, Biol. Reprod. 60
(1999) 1231–1238.
[115] E. Hirsch, R.A. Muhle, G.M. Mussalli, R. Blanchard, Bacterially induced
preterm labor in the mouse does not require maternal interleukin1 signaling, Am. J. Obstet. Gynecol. 186 (2002) 523–530.
[116] E. Hirsch, Y. Filipovich, M. Mahendroo, Signaling via the type I IL-1 and TNF
receptors is necessary for bacterially induced preterm labor in a murine
model, Am. J. Obstet. Gynecol. 194 (2006) 1334–1340.
[117] P.L.J. Fidel, r, R. Romero, J. Cutright, N. Wolf, R. Gomez, H. Araneda, et al.,
Treatment with the interleukin-I receptor antagonist and soluble tumor
necrosis factor receptor Fc fusion protein does not prevent endotoxininduced preterm parturition in mice, J. Soc. Gynecol. Invest. 4 (1997)
22–26.
[118] S. Girard, L. Tremblay, M. Lepage, G. Sebire, IL-1 receptor antagonist protects
against placental and neurodevelopmental defects induced by maternal
inflammation, J. Immunol. (Baltimore, Md: 1950) 184 (2010) 3997–4005.
[119] R.M. Tribe, P. Moriarty, A. Dalrymple, A.A. Hassoni, L. Poston, Interleukin1beta induces calcium transients and enhances basal and store operated
calcium entry in human myometrial smooth muscle, Biol. Reprod. 68 (2003)
1842–1849.
[120] A. Dalrymple, D.M. Slater, L. Poston, R.M. Tribe, Physiological induction of
transient receptor potential canonical proteins, calcium entry channels, in
human myometrium: influence of pregnancy, labor, and interleukin-1 beta, J.
Clin. Endocrinol. Metabol. 89 (2004) 1291–1300.
[121] S. Santtila, K. Savinainen, M. Hurme, Presence of the IL-1RA allele 2 (IL1RN*2)
is associated with enhanced IL-1beta production in vitro, Scand. J. Immunol.
47 (1998) 195–198.
[122] M. Hurme, S. Santtila, IL-1 receptor antagonist (IL-1Ra) plasma levels are coordinately regulated by both IL-1Ra and IL-1beta genes, Eur. J. Immunol. 28
(1998) 2598–2602.
[123] N.M. Jones, C. Holzman, K.H. Friderici, K. Jernigan, H. Chung, J. Wirth, et al.,
Interplay of cytokine polymorphisms and bacterial vaginosis in the etiology
of preterm delivery, J. Reprod. Immunol. 87 (2010) 82–89.
[124] A.P. Murtha, A. Nieves, E.R. Hauser, G.K. Swamy, B.A. Yonish, T.R. Sinclair, et al.,
Association of maternal IL-1 receptor antagonist intron 2 gene
polymorphism and preterm birth, Am. J. Obstet. Gynecol. 195 (2006) 1249–
1253.
[125] J.H. Chaves, A. Babayan, M. Bezerra Cde, I.M. Linhares, S.S. Witkin, Maternal
and neonatal interleukin-1 receptor antagonist genotype and pregnancy
outcome in a population with a high rate of pre-term birth, Am. J. Reprod.
Immunol. 60 (2008) 312–317.
[126] H. Chen, L.M. Wilkins, N. Aziz, C. Cannings, D.H. Wyllie, C. Bingle, et al., Single
nucleotide polymorphisms in the human interleukin-1B gene affect
transcription according to haplotype context, Hum. Mol. Genet. 15 (2006)
519–529.
[127] M. Schmid, P. Haslinger, S. Stary, H. Leipold, C. Egarter, C. Grimm, Interleukin1 beta gene polymorphisms and preterm birth, Eur. J. Obstet. Gynecol.
Reprod. Biol. 165 (2012) 33–36.
[128] A. Dubicke, E. Fransson, G. Centini, E. Andersson, B. Bystrom, A. Malmstrom,
et al., Pro-inflammatory and anti-inflammatory cytokines in human preterm
and term cervical ripening, J. Reprod. Immunol. 84 (2010) 176–185.
49
[129] Y. Tanaka, H. Narahara, N. Takai, J. Yoshimatsu, T. Anai, I. Miyakawa,
Interleukin-1beta and interleukin-8 in cervicovaginal fluid during pregnancy,
Am. J. Obstet. Gynecol. 179 (1998) 644–649.
[130] R.J. Ruiz, N. Jallo, C. Murphey, C.N. Marti, E. Godbold, R.H. Pickler, Second
trimester maternal plasma levels of cytokines IL-1Ra, Il-6 and IL-10 and
preterm birth, J. Perinatol. 32 (2012) 483–490.
[131] R.B. Kalish, S. Vardhana, M. Gupta, S.T. Chasen, S.C. Perni, S.S. Witkin,
Interleukin-1 receptor antagonist gene polymorphism and multifetal
pregnancy outcome, Am. J. Obstet. Gynecol. 189 (2003) 911–914.
[132] Y.J. Heng, S. Liong, M. Permezel, G.E. Rice, M.K. Di Quinzio, H.M. Georgiou, The
interplay of the interleukin 1 system in pregnancy and labor, Reprod. Sci. 21
(2014) 122–130.
[133] S. Girard, A.E. Heazell, H. Derricott, S.M. Allan, C.P. Sibley, V.M. Abrahams,
et al., Circulating cytokines and alarmins associated with placental
inflammation in high-risk pregnancies, Am. J. Reprod. Immunol. 72 (2014)
422–434.
[134] G.J. Haluska, T.R. Wells, J.J. Hirst, R.M. Brenner, D.W. Sadowsky, M.J. Novy,
Progesterone receptor localization and isoforms in myometrium, decidua,
and fetal membranes from rhesus macaques: evidence for functional
progesterone withdrawal at parturition, J. Soc. Gynecol. Invest. 9 (2002) 125–
136.
[135] A.E. Roberson, K. Hyatt, C. Kenkel, K. Hanson, D.A. Myers, Interleukin 1beta
regulates progesterone metabolism in human cervical fibroblasts, Reprod.
Sci. 19 (2012) 271–281.
[136] J.E. Young, C.I. Friedman, D.R. Danforth, Interleukin-1 beta modulates
prostaglandin and progesterone production by primate luteal cells in vitro,
Biol. Reprod. 56 (1997) 663–667.
[137] M. McLean, A. Bisits, J. Davies, R. Woods, P. Lowry, R. Smith, A placental clock
controlling the length of human pregnancy, Nat. Med. 1 (1995) 460–463.
[138] M. McLean, R. Smith, Corticotrophin-releasing hormone and human
parturition, Reproduction (Cambridge, England) 121 (2001) 493–501.
[139] J.R. Challis, S.J. Lye, W. Gibb, W. Whittle, F. Patel, N. Alfaidy, Understanding
preterm labor, Ann. N.Y. Acad. Sci. 943 (2001) 225–234.
[140] J.R. Challis, S.K. Smith, Fetal endocrine signals and preterm labor, Biol.
Neonate 79 (2001) 163–167.
[141] C.A. Sandman, P.D. Wadhwa, A. Chicz-DeMet, C. Dunkel-Schetter, M. Porto,
Maternal stress, HPA activity, and fetal/infant outcome, Ann. N.Y. Acad. Sci.
814 (1997) 266–275.
[142] A. Uh, R.C. Nicholson, G.V. Gonzalez, C.F. Simmons, A. Gombart, R. Smith,
et al., Lipopolysaccharide stimulation of trophoblasts induces corticotropinreleasing hormone expression through MyD88, Am. J. Obstet. Gynecol. 199
(317) (2008) e1–e6.
[143] D. Markovic, M. Vatish, M. Gu, D. Slater, R. Newton, H. Lehnert, et al., The
onset of labor alters corticotropin-releasing hormone type 1 receptor variant
expression in human myometrium: putative role of interleukin-1beta,
Endocrinology 148 (2007) 3205–3213.
[144] I. Kossintseva, S. Wong, E. Johnstone, L. Guilbert, D.M. Olson, B.F. Mitchell,
Proinflammatory cytokines inhibit human placental 11beta-hydroxysteroid
dehydrogenase type 2 activity through Ca2+ and cAMP pathways, Am. J.
Physiol. Endocrinol. Metabol. 290 (2006) E282–E288.
[145] U. Friebe-Hoffmann, D.M. Baston, T.K. Hoffmann, J.P. Chiao, P.N. Rauk, The
influence of interleukin-1beta on oxytocin signalling in primary cells of
human decidua, Regul. Pept. 142 (2007) 78–85.
[146] M. Breuiller-Fouche, C. Moriniere, E. Dallot, S. Oger, R. Rebourcet, D. Cabrol,
et al., Regulation of the endothelin/endothelin receptor system by
interleukin-1{beta} in human myometrial cells, Endocrinology 146 (2005)
4878–4886.
[147] B.W. Donesky, M. Dias de Moura, C. Tedeschi, A. Hurwitz, E.Y. Adashi,
D.W. Payne, Interleukin-1beta inhibits steroidogenic bioactivity in
cultured rat ovarian granulosa cells by stimulation of progesterone
degradation and inhibition of estrogen formation, Biol. Reprod. 58 (1998)
1108–1116.
[148] A.G. Braundmeier, R.A. Nowak, Cytokines regulate matrix metalloproteinases
in human uterine endometrial fibroblast cells through a mechanism that
does not involve increases in extracellular matrix metalloproteinase inducer,
Am. J. Reprod. Immunol. 56 (2006) 201–214.
[149] M. Watari, H. Watari, M.E. DiSanto, S. Chacko, G.P. Shi, J.F. Strauss 3rd,
Pro-inflammatory cytokines induce expression of matrix-metabolizing
enzymes in human cervical smooth muscle cells, Am. J. Pathol. 154 (1999)
1755–1762.
[150] D. Stygar, H. Wang, Y.S. Vladic, G. Ekman, H. Eriksson, L. Sahlin, Increased level
of matrix metalloproteinases 2 and 9 in the ripening process of the human
cervix, Biol. Reprod. 67 (2002) 889–894.
[151] K.W. Marvin, J.A. Keelan, R.L. Eykholt, T.A. Sato, M.D. Mitchell, Expression of
angiogenic and neurotrophic factors in the human amnion and
choriodecidua, Am. J. Obstet. Gynecol. 187 (2002) 728–734.
[152] V.V. Snegovskikh, F. Schatz, F. Arcuri, P. Toti, U.A. Kayisli, W. Murk, et al., Intraamniotic infection upregulates decidual cell vascular endothelial growth
factor (VEGF) and neuropilin-1 and -2 expression: implications for infectionrelated preterm birth, Reprod. Sci. 16 (2009) 767–780.
[153] S.A. Ibrahim, W.E.T. Ackerman, T.L. Summerfield, C.J. Lockwood, F. Schatz, D.A.
Kniss, Inflammatory gene networks in term human decidual cells define a
potential signature for cytokine-mediated parturition, Am. J. Obstet. Gynecol.
(2015) .
50
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
[154] J.C. Condon, P. Jeyasuria, J.M. Faust, C.R. Mendelson, Surfactant protein
secreted by the maturing mouse fetal lung acts as a hormone that signals the
initiation of parturition, Proc. Nal. Acad. Sci. U. S. A. 101 (2004) 4978–4983.
[155] H. Zheng, D. Fletcher, W. Kozak, M. Jiang, K.J. Hofmann, C.A. Conn, et al.,
Resistance to fever induction and impaired acute-phase response in
interleukin-1 beta-deficient mice, Immunity 3 (1995) 9–19.
[156] P. Li, H. Allen, S. Banerjee, S. Franklin, L. Herzog, C. Johnston, et al., Mice
deficient in IL-1 beta-converting enzyme are defective in production of
mature IL-1 beta and resistant to endotoxic shock, Cell 80 (1995) 401–411.
[157] L.R. Leon, C.A. Conn, M. Glaccum, M.J. Kluger, IL-1 type I receptor mediates
acute phase response to turpentine, but not lipopolysaccharide, in mice, Am.
J. Physiol. 271 (1996) R1668–75.
[158] S.J. Abbondanzo, E.B. Cullinan, K. McIntyre, M.A. Labow, C.L. Stewart,
Reproduction in mice lacking a functional type 1 IL-1 receptor, Endocrinology
137 (1996) 3598–3601.
[159] C.A. Dinarello, J.W. van der Meer, Treating inflammation by blocking
interleukin-1 in humans, Sem. Immunol. 25 (2013) 469–484.
[160] K. Leitner, M. Al Shammary, M. McLane, M.V. Johnston, M.A. Elovitz, I. Burd,
IL-1 receptor blockade prevents fetal cortical brain injury but not preterm
birth in a mouse model of inflammation-induced preterm birth and perinatal
brain injury, Am. J. Reprod. Immunol. 71 (2014) 418–426.
[161] M. Ostensen, M. Khamashta, M. Lockshin, A. Parke, A. Brucato, H. Carp, et al.,
Anti-inflammatory and immunosuppressive drugs and reproduction, Arthr.
Res. Ther. 8 (2006) 209.
[162] S.C. Kim, S. Hernandez-Diaz, Editorial safety of immunosuppressive drugs in
pregnant women with systemic inflammatory diseases, Arthr. Rheumatol.
(Hoboken, NJ) 66 (2014) 246–249.
[163] G. Gaunt, K. Ramin, Immunological tolerance of the human fetus, Am. J.
Perinatol. 18 (2001) 299–312.
[164] P.A. Costeas, A. Koumouli, A. Giantsiou-Kyriakou, A. Papaloizou, L. Koumas,
Th2/Th3 cytokine genotypes are associated with pregnancy loss, Hum.
Immunol. 65 (2004) 135–141.
[165] J.A. Poole, H.N. Claman, Immunology of pregnancy: Implications for the
mother, Clin. Rev. Allergy Immunol. 26 (2004) 161–170.
[166] J.A. Keelan, S. Khan, F. Yosaatmadja, M.D. Mitchell, Prevention of
inflammatory activation of human gestational membranes in an ex vivo
model using a pharmacological NF-kappaB inhibitor, J. Immunol. (Baltimore,
Md: 1950) 183 (2009) 5270–5278.
[167] A.Y. Shahin, I.M. Hassanin, A.M. Ismail, J.S. Kruessel, J. Hirchenhain, Effect of
oral N-acetyl cysteine on recurrent preterm labor following treatment for
bacterial vaginosis, Int. J. Gynaecol. Obstet. 104 (2009) 44–48.
[168] M. Zafarullah, W.Q. Li, J. Sylvester, M. Ahmad, Molecular mechanisms of Nacetylcysteine actions, Cell. Mol. Life Sci.: CMLS 60 (2003) 6–20.
[169] J.E. Mijovic, T. Zakar, D.B. Zaragoza, D.M. Olson, Tyrphostins inhibit
lipopolysaccharide induced preterm labor in mice, J. Perinat. Med. 30 (2002)
297–300.
[170] P.Y. Ng, D.J. Ireland, J.A. Keelan, Drugs to block cytokine signaling for the
prevention and treatment of inflammation-induced preterm birth, Front.
Immunol. 6 (166) (2015) .
[171] H.L. LaMarca, P.R. Dash, K. Vishnuthevan, E. Harvey, D.E. Sullivan, C.A. Morris,
et al., Epidermal growth factor-stimulated extravillous cytotrophoblast
motility is mediated by the activation of PI3-K, Akt and both p38 and p42/
44 mitogen-activated protein kinases, Hum. Reprod. 23 (2008) 1733–1741.
[172] C. Vaillancourt, D. Lanoix, B. Le, F. ellego, G. Daoud, J. Lafond, Involvement of
MAPK signalling in human villous trophoblast differentiation, Mini Rev. Med.
Chem. 9 (2009) 962–973.
[173] S.C. Miller, R. Huang, S. Sakamuru, S.J. Shukla, M.S. Attene-Ramos, P. Shinn,
et al., Identification of known drugs that act as inhibitors of NF-kappaB
signaling and their mechanism of action, Biochem. Pharmacol. 79 (2010)
1272–1280.
[174] E. Goupil, D. Tassy, C. Bourguet, C. Quiniou, V. Wisehart, D. Petrin, et al., A
novel biased allosteric compound inhibitor of parturition selectively impedes
the prostaglandin F2alpha-mediated Rho/ROCK signaling pathway, J. Biol.
Chem. 285 (2010) 25624–25636.
[175] B. Bottcher, R.M. Laterza, L. Wildt, R.J. Seufert, K.J. Buhling, C.F. Singer, et al., A
first-in-human study of PDC31 (prostaglandin F2alpha receptor inhibitor) in
primary dysmenorrhea, Hum. Reprod. 29 (2014) 2465–2473.
[176] J.M. McDonnell, A.J. Beavil, G.A. Mackay, B.A. Jameson, R. Korngold, H.J. Gould,
et al., Structure based design and characterization of peptides that inhibit IgE
binding to its high-affinity receptor, Nat. Struct. Biol. 3 (1996) 419–426.
[177] N. Zhou, Z. Luo, J. Luo, X. Fan, M. Cayabyab, M. Hiraoka, et al., Exploring the
stereochemistry of CXCR4-peptide recognition and inhibiting HIV-1 entry
with D-peptides derived from chemokines, J. Biol. Chem. 277 (2002) 17476–
17485.
[178] L. Rihakova, C. Quiniou, F.F. Hamdan, R. Kaul, S. Brault, X. Hou, et al., VRQ397
(CRAVKY): a novel noncompetitive V2 receptor antagonist, Am. J. Physiol.
Regulat. Integr. Comp. Physiol. 297 (2009) R1009–R1018.
[179] A. Christopoulos, L.T. May, V.A. Avlani, P.M. Sexton, G-protein-coupled
receptor allosterism: the promise and the problem(s), Biochem. Soc. Trans.
32 (2004) 873–877.
[180] H. Blencowe, S. Cousens, D. Chou, M. Oestergaard, L. Say, A.B. Moller, et al.,
Born too soon: the global epidemiology of 15 million preterm births, Reprod.
Health 10 (Suppl. 1) (2013) S2.
[181] D.M. Olson, I. Christiaens, S. Gracie, Y. Yamamoto, B.F. Mitchell, Emerging
tocolytics: challenges in designing and testing drugs to delay preterm
delivery and prolong pregnancy, Exp. Opin. Emerg. Drugs 13 (2008) 695–707.
[182] L. Duley, S. Uhm, S. Oliver, Top 15 UK research priorities for preterm birth,
Lancet 383 (2014) 2041–2042.
[183] D. Baird, The influence of social and economic factors on stillbirths and
neonatal deaths, Br. J. Obstet. Gynaecol. 52 (1945) 339–366.
[184] J.E. Norman, A.H. Shennan, Prevention of preterm birth—why can’t we do any
better, Lancet 381 (2013) 184–185.
[185] C. Quiniou, P. Sapieha, I. Lahaie, X. Hou, S. Brault, M. Beauchamp, et al.,
Development of a novel noncompetitive antagonist of IL-1 receptor, J.
Immunol. 180 (2008) 6977–6987.
[186] D.S. Abbott, S.K. Radford, P.T. Seed, R.M. Tribe, A.H. Shennan, Evaluation of a
quantitative fetal fibronectin test for spontaneous preterm birth in
symptomatic women, Am. J. Obstet. Gynecol. 208 (122) (2013) e1–e6.
[187] N. Abbott DaH, P. Seed, P. Bennett, M. Chandiramani, A. David, J. Girling, J.
Norman, S. Stock, R. Tribe, A. Shennan, PPO.01EQUIPP: Evaluation of Fetal
Fibronectin with a novel bedside Quantitative Instrument for the Prediction
of Preterm birth. Archives of disease in childhood Fetal and neonatal edition,
99 (Suppl. 1), (2014), A150–A151.
[188] D.S. Abbott, N.L. Hezelgrave, P.T. Seed, J.E. Norman, A.L. David, P.R. Bennett,
et al., Quantitative fetal fibronectin to predict preterm birth in asymptomatic
women at high risk, Obstet. Gynecol. 125 (2015) 1168–1176.
[189] H. Khambay, L.A. Bolt, M. Chandiramani, G. De, A. reeff, J.E. Filmer, A.H.
Shennan, The Actim Partus test to predict pre-term birth in asymptomatic
high-risk women, J. Obstet. Gynaecol. 32 (2012) 132–134.
Mathieu Nadeau-Vallée is a PhD student in Pharmacology at Université de Montréal. Highly driven, he accessed
PhD straight from BSc (with Honours). Mathieu is
interested in the identification of novel targets implicated
in preterm birth for the development of new and safe
therapeutics to prevent this condition. His most recent
work describes the identification of a novel molecule to
prevent preterm birth and was published in The Journal of
Immunology . His researches are supported by the
Canadian Institutes of Health Research (IRSC), the Fonds
de Recherche en Santé du Québec (FRQS) and the Vision
Health Research Network.
Dima Obari is a high-achieving PhD student in Pharmacology at Université de Montréal and an independent
scientific and medical illustrator. She has earned her M.Sc.
in Clinical Neuroscience at University College London
with Honours in 2014. Currently, she is investigating the
effect of vascular disease on the brain in the laboratory of
Dr. Hélène Girouard, and her work is supported by the
Arterial Hypertension Society of Quebec (SQHA). Dima is
interested to collaborate with innovative scientists and to
produce scientific illustrations for groundbreaking projects (contact at: [email protected]).
Christiane Quiniou has a M.Sc. in applied microbiology
from Institut Armand-Frappier and a PhD degree in
Biochemistry from University of Montreal. Dr. Quiniou
accumulated 15 years of experience in in vitro pharmacological characterization of allosteric modulators and
conceived the rytvela (101.10) peptide. Her work was
supported by the Hearth and Stroke Foundation and the
Fonds de la Recherche en Santé du Québec.
William D. Lubell received his B.A. from Columbia
College (1984) and Ph.D. under the supervision of
Professor Henry Rapoport at the University of California,
Berkeley (1989). As a Japan Society for the Promotion of
Science Fellow (1990–1991), he studied enantioselective
catalysis with Professor Ryoji Noyori at Nagoya University, Japan. In 1991, he joined the Department of Chemistry
at the Université de Montréal, Canada, where he is Full
Professor. Co-author of 200 scientific publications, he
researches the synthesis and use of heterocycles, amino
acids and peptide mimics in medicinal chemistry and
peptide science. Associate Editor of Organic Letters, and
editorial board member of journals in peptide and drug
design, his honors include the Boehringer Ingelheim Young Investigator Award, the
DuPont Canada Educational Aid Grant, the Danish National Bank Award, the Merck
Therapeutic Research Award and in 2013 the Canadian Society for Chemistry
Bernard Belleau Award for achievements in medicinal chemistry. Originator of
Molecules of Life (www.moleculesoflife.ca), he explores experiential education
techniques for teaching elementary school students about molecules.
M. Nadeau-Vallée et al. / Cytokine & Growth Factor Reviews 28 (2016) 37–51
David M. Olson, Ph.D., FRCOG is an active researcher,
teacher and is sought out as a lecturer at universities
around the world. His work is dedicated to improving
maternal-child health, especially discovering new means
to diagnose and treat preterm birth. Educated at
Augustana College (Sioux Falls, SD), the University of
Minnesota, St. Louis University, and Western University
(London, Canada), he directed or co-directed the University of Alberta Perinatal Research Centre, the CIHR Group
in Perinatal Health and Disease, the CIHR Strategic
Training Initiative in Maternal-Fetal-Newborn Health
Research, and the AIHS Interdisciplinary Preterm Birth
and Healthy Outcomes Team. He currently directs the
international GAPPS Inflammatory Pathways to Preterm Birth and PREBIC Optimal
Pregnancy Environment Risk Assessment (OPERA) teams. He is a founding board
member of the Child Health Research Institute and The Mogenson Trust (both
Western University), The Alberta Centre for Child, Family and Community Research
and has been elected to serve as an officer in several national and international
societies, including President of the Canadian Investigators in Reproduction. He
founded and organized the Western Perinatal Research Meeting in Banff from
1993–2013 and then the Canadian National Perinatal Research Meeting in 2014.
Raising >$30 M for research, he has supervised >140 trainees and published
>150 papers. He is patenting intellectual property and translating it to improve
women’s pregnancy and newborn health. In 2009 he was elected a Fellow ad
eundem of the Royal College of Obstetricians and Gynaecologists.
Sylvie Girard completed her PhD in Immunology at
Université de Sherbrooke in 2010 and begun her
postdoctoral work at the Faculty of Life Sciences and
the Maternal and Fetal Health Research Center, University
of Manchester, UK (2011–2013). Following a short
postdoctoral fellowship in reproductive immunology
(Yale University, USA; 2014) she established her independent research group at the Sainte-Justine Hospital
Research Centre, in Montreal, Qc, Canada (2014). She is
an assistant professor (Department of Obstetrics &
Gynecology) at Université de Montréal, Qc, Canada. Her
research group studies pathological pregnancies, primarily the impact of in utero inflammation on the placenta as
well as the long-term impact on the development of the neonate.
51
Sylvain Chemtob is a reputed neonatal pharmacologist
and physiologist, with expertise on mechanisms implicated in ischemic retinopathies and other conditions
involving inflammation. He has also initiated a new
technology to develop peptidomimetic drugs that target
membrane receptors; some compounds are licensed to
industry, and one which successfully completed Phase Ib
clinical trial is Phase II-ready (PDC Biotech). His seminal
work also triggered the approval (EMEA [2004], FDA
[2006]) of new therapies for closure of ductus arteriosus,
which is now standard of care. Sylvain Chemtob is author
of over 250 articles reported in major journals, as well as
inventor of 10 patents. He has trained so far 46 graduate
students and 29 post-graduate fellows (MDs and PhDs). He has received numerous
awards and is a member of the Canadn Academy of Health Sciences. He holds a
Canada Research Chair (Vision Science) and the Leopoldine Wolfe Chair in
Translational Research in age-related macular degeneration at Université de
Montreal.