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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.