Download PI3K and negative regulation of TLR signaling

358
Opinion
TRENDS in Immunology
Vol.24 No.7 July 2003
PI3K and negative regulation of TLR
signaling
Taro Fukao and Shigeo Koyasu
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582,
Japan
Excessive immune responses are detrimental to the
host and negative feedback regulation is crucial for the
maintenance of immune-system integrity. Recent
studies have shown that phosphoinositide 3-kinase
(PI3K) is an endogenous suppressor of interleukin-12
(IL-12) production triggered by Toll-like receptor (TLR)
signaling and limits excessive Th1 polarization. Unlike
IRAK-M (IL-1 receptor-associated kinase-M) and SOCS-1
(suppressor of cytokine signaling-1) that are induced by
TLR signaling and function during the second or continuous exposure to stimulation, PI3K functions at the
early phase of TLR signaling and modulates the magnitude of the primary activation. Thus, PI3K, IRAK-M and
SOCS-1 have unique roles in the gate-keeping system,
preventing excessive innate immune responses.
Innate immune reactions are triggered through Toll-like
receptors (TLRs) that recognize a variety of microbial
products collectively termed pathogen-associated molecular patterns (PAMPs) [1– 3]. Stimulation through TLRs by
PAMPs, such as lipopolysaccharide (LPS) (endotoxin),
triggers production of various cytokines, including interleukin-12 (IL-12), which is a crucial inducer of Th1
responses [4,5]. The resultant inflammatory response is
essential for the eradication of infectious microorganisms.
However, excessive and prolonged activation of innate
immunity is harmful to the host and, in some cases, even
fatal, owing to severe tissue damage and circulatory
failure [1]. To prevent such an undesirable outcome, the
innate immune system should have a gate-keeping system
that ensures a response with an appropriate magnitude to
pathogens and/or avoids responses to multiple waves of
pathogenic stimuli. Endotoxin tolerance is one such
mechanism to avoid sustained stimuli: continuous
exposure to sublethal doses of endotoxin reduces febrile
responses and the host becomes resistant to subsequent
challenges with endotoxin at a lethal dose to untreated
hosts [6,7].
The hosts are able to achieve endotoxin tolerance
through multiple processes, including downregulation of
the LPS receptor [TLR4 – MD2 (myeloid differentiation 2)
complex] [8] and limited activation of NF-kB [9]. The
recent discovery of IL-1 associated kinase-M (IRAK-M),
which is inducible on TLR activation, has revealed a
negative regulatory mechanism for TLR signaling [10]. In
Corresponding author: Shigeo Koyasu ([email protected]).
addition, suppressor of cytokine signaling-1 (SOCS-1) is an
additional inducible negative regulator of TLR signaling,
although its induction occurs only through TLR4 [11,12].
These findings thus present potential new molecular
mechanisms for tolerance in innate immune responses.
Studies on the role of phosphoinositide 3-kinases
(PI3Ks) in innate immunity have also raised a possible
safety system to control the magnitude of cellular
responses to pathogens [13,14]. This system differs from
the described tolerance systems, in that PI3Ks negatively
regulate TLR signaling at an earlier phase and function at
the first encounter to pathogens. In this Opinion, we
discuss these gate-keeping mechanisms in innate immunity and the future direction of studies, including possible
therapeutic approaches using manipulation of such
negative feedback regulatory mechanisms in innate
immune responses.
PI3K-mediated negative feedback regulation of IL-12
production
The amount of IL-12 produced by stimulation through
TLRs is crucial in the balance between Th1 and Th2
responses [4,5]. Mice lacking the p85a regulatory subunit
of class IA PI3K (PI3K2/2 mice) show impaired immunity
against the intestinal nematode, Strongyloides venezuelensis, probably as a result of an impaired Th2 response
[15]. Furthermore, PI3K2/2 mice on a BALB/c background
demonstrate enhanced Th1 responses and are resistant to
Leishmania major infection, unlike wild-type mice [13].
These observations indicate that class IA PI3K is important in the Th1 versus Th2 balance in vivo and controls
induction of the Th2 response and/or suppression of the
Th1 response. In fact, splenic and bone marrow-derived
dendritic cells (DCs) from PI3K2/2 mice produce more
IL-12 than wild-type DCs [13]. Furthermore, wortmannin,
a specific inhibitor of PI3Ks, also increased IL-12 synthesis
by wild-type DCs in vitro [13]. Thus, overproduction of
IL-12 by DCs is probably the main cause of the skewed Th1
response in PI3K2/2 mice. These observations indicate
that PI3K has a crucial negative regulatory role during
induction of the Th1 immune response by suppressing the
production of IL-12 by DCs. Although individual PI3K
isoforms exhibit non-redundant specific functions [16 – 20]
and in vivo observations are limited to the role of class IA
PI3K, pharmacological experiments raised a possible
contribution of other class of PI3Ks in the regulation of
IL-12 production.
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Opinion
TRENDS in Immunology
359
Vol.24 No.7 July 2003
Mechanism of PI3K-mediated suppression of IL-12
production
Notably, PI3Ks are activated in DCs by many distinct
stimuli, including LPS, peptidoglycan, CpG-oligodeoxynucleotide (CpG-ODN), CD40L and RANKL (receptor
activator of NF-kB ligand), all of which induce IL-12
production [13,21 – 25] (Table 1). TLRs thus simultaneously mediate both positive and negative regulatory
signaling pathways for IL-12 production in DCs.
Signal transduction pathways that activate PI3K
downstream of TLRs are not completely characterized
but are classified into at least two pathways, namely
‘shared’ and ‘specific’ pathways [2,3,26]. Although activation of PI3K downstream of TLR2 is mediated in a
Rac1-dependent manner [22], it is unclear if such a
Rac-1-dependent signaling cascade is shared by all
members of the TLR family. Nonetheless, PI3K is activated
after triggering of many TLR members [13] (Table 1),
suggesting the presence of ‘shared’ signaling pathway(s)
for TLR-mediated activation of PI3K (Fig. 1). MyD88,
TOLLIP (Toll-interacting protein), IRAK and TRAF6
[tumor necrosis factor (TNF) receptor-associated factor 6]
are involved in such ‘shared’ signaling pathway(s) [2,3].
However, Toll– IL-1 receptor domain-containing adaptor
protein (TIRAP) [also known as MyD88-adaptor-like
(MAL)] and Toll– IL-1 receptor domain-containing adaptor
inducing IFN-b [TRIF, also known as TIR-containing
adaptor molecule-1 (TICAM-1)] are involved in specific
pathways [26]. In TLR4 signaling, TAK1 (transforming
growth factor b-activated kinase 1) and TRAF6 pathways
are operative in PI3K activation downstream of TLR4
[27,28]. More recently, interaction of PI3K with MyD88 in
response to LPS has been reported, demonstrating the
importance of such ‘shared’ signaling in the PI3K pathway
[29]. However, there is little information on the specificity
of individual PI3K isoform to TLRs.
In DCs, PI3K seems to block the p38 activation
pathway. Inhibition of PI3K results in an increase in the
activity of p38 mitogen-activated protein kinase (MAPK)
that is essential for transcriptional activation of both the
IL-12 p35 and p40 genes [13,30], implying that direct
inhibition of p38 MAPK by PI3K signaling contributes to
the negative regulatory mechanism. Although it has not
been shown how PI3K suppresses the p38 pathway, recent
reports provide us with some hints (Fig. 1). Protein
kinase B (PKB)-mediated phosphorylation of apoptosis
signal-regulating kinase 1 (ASK1), one of the MAPK
kinase kinases (MAPKK-Ks), blocks ASK1 kinase activity,
leading to suppression of MAPK kinase 3 (MKK3) or
MKK6, upstream regulators of p38 [31]. Moreover, PKB
blocks kinase activity of MEKK3, another MAPKK-K
upstream of p38 [32]. Because activation of PKB is
positively regulated by PI3K [33], inhibition of PI3K, or
lack of PI3K, upregulates p38 activity in DCs [13].
Consistent with the observation in DCs, the PI3K– PKB
pathway in monocytes also suppresses both MAPKs and
NF-kB cascades in response to LPS, resulting in decreased
production of TNF-a [14]. Because PI3K suppresses p38 in
DCs [13] and MAPK and NF-kB pathways in monocytes
[14], the role of PI3K as a negative regulator of TLR
Table 1. Selected references of pro- or anti-inflammatory action of TLR-triggered PI3K in DCs and monocytes or macrophagesa
TLR family
Cell type (species)
Action of PI3K
Refs
Pro- or anti-inflammatory
TLR2
Primary monocyte-derived DCs (human)
Monocytic cell line (THP-1) (human)
Macrophage cell line (RAW264.7)
(mouse)
Primary BM-derived and splenic DCs
(mouse)
Primary monocyte-derived DCs (human)
Macrophage cell line (RAW264.7)
(mouse)
Primary BM-derived and splenic DCs
(mouse)
Primary alveolar macrophage (human)
Signal transduction for cytokine expression
Signal transduction for NF-kB activation
Signal transduction for cytokine expression
[40]
[22]
[41]
Proinflammatory
Suppression of IL-12 production
[13]
Anti-inflammatory
Signal transduction for cytokine expression
Signal transduction for cytokine expression
[40]
[41]
Proinflammatory
Inhibition of IL-12 production by p38
suppression
Suppression of PGE2 by negative regulation of
COX2 mRNA stability
Inhibition of TNF-a and TF production by
suppression of NF-kB and MAPKs
Negative regulation of NO production by
suppression of NOS2 induction
Negative regulation of NO by suppression of
NOS2 induction and inhibition of
TNF-a Production
Suppression of TNF-a and NO production in
response to second activation by LPS
(endotoxin tolerance?)
Signal transduction for IL-12 production by
induction of CpG-ODN internalization
Signal transduction for IL-12 production
Induction of chemotaxis in response to CpG-ODN
Suppression of IL-12 production (observed in
gene targeting of p85 subunit of class IA PI3K)
[13]
TLR4
Monocyte cell line (THP-1) (human)
Macrophage cell line (RAW264.7)
(mouse)
Primary peritoneal macrophage (mouse)
Macrophage cell line (RAW264.7)
(mouse)
TLR9
Primary BM-derived DCs (mouse)
Primary splenic DCs (mouse)
Primary peritoneal macrophage (mouse)
Primary BM-derived and splenic DCs
(mouse)
a
[42]
Anti-inflammatory
[14]
[43]
[44]
[45]
[46]
Proinflammatory
[47]
[48]
[13]
Anti-inflammatory
Abbreviations: BM, bone marrow; COX2, cyclooxygenase 2; DCs, dendritic cells; IL-12, interleukin-12; LPS, lipopolysaccharide; NOS2, inducible NO synthase; MAPKs,
mitogen-activated protein kinases; NO, nitric oxide; ODN, oligodeoxynucleotide; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; TF, tissue factor; TLR, Toll-like
receptor; TNF-a, tumor necrosis factor-a.
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360
Opinion
TRENDS in Immunology
Vol.24 No.7 July 2003
TLR2/4
PIP2
PIP3
Rac1
MyD88
TOLLIP
PDK
PI3K
IRAK
TAK1
pIRAK
PKB
TRAF6
Suppression
IKKβ
MAP3K
MKK3/6
MKK4/7
MKK1/2
p38
JNK
ERK
NF-κB
Inflammatory cytokine gene expression
TRENDS in Immunology
Fig. 1. Negative regulation of TLR signaling by PI3K in innate immune cells. PAMPs-triggered TLR signaling activates NF-kB and mitogen-activated protein kinase (MAPK)
cascades. Simultaneously, TLRs mediate PI3K activation that suppresses p38 or MAPKs and NF-kB in DCs or monocytes, respectively. Inhibition of these signaling cascades
by PI3K is possibly mediated by PKB, and limits the production of inflammatory cytokines [13,14]. Reported mechanisms of coupling of PI3K to TLR2 (red arrow) or TLR4
(purple arrow) are shown. Abbreviations: DCs, dendritic cells; ERK, extracellular-signal regulated kinase; IKKb, IkB kinase b; IRAK, interleukin-1 receptor associated kinase;
JNK, c-Jun N-terminal kinase; MAPKs, mitogen-activated protein kinases; MKK, MAPK kinase; PAMPs, pathogen-associated molecular patterns; PDK, phosphoinositidedependent kinase; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; pIRAK, phosphorylated
IRAK; PKB, protein kinase B; TAK1, transforming growth factor b-activated kinase 1; TLR, Toll-like receptor; TOLLIP, Toll-interacting protein; TRAF6, tumor necrosis factor
receptor-associated factor 6.
signaling in innate immunity might not be restricted to
IL-12 production (Fig. 1).
There are several reports demonstrating a proinflammatory role for PI3K, such as positive regulation of NF-kB
transactivation [22,34] (Table 1). NF-kB transactivation
by the PI3K cascade in TLR2-mediated signaling is
independent of IkBa (inhibitor of NF-kBa) degradation
and triggered by PI3K-pathway-mediated p65 phosphorylation [22,34]. Because NF-kB activation is required for the
transcription of both IL-12 p35 and p40 [4,5], hyperexpression of IL-12 by PI3K inhibition seems inconsistent
with such reports. According to Guha and Mackman [14],
however, inhibition of PI3K augments the phosphorylation
and degradation of IkBa, resulting in nuclear localization
of NF-kB in monocytes. Such qualitative differences in the
activation pathways of NF-kB might account for the
distinct effects of PI3K. Functional relationships between
these pathways downstream of TLRs should be examined.
Negative regulation of innate immunity and Th1 reaction
The recent discoveries of IRAK-M- and SOCS-1-dependent
negative regulatory mechanisms in TLR-signaling pathways suggest distinct types of safety mechanisms for
controlling inflammatory responses because IRAK-Mand SOCS-1-deficient macrophages produce enhanced
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amounts of inflammatory cytokines, including IL-12
[10 –12]. Although SOCS-1-dependent negative regulation
seems specific for TLR4 signaling [11,12], PI3K, IRAK-M
and SOCS-1 probably contribute to negative signaling
cascades in TLR signaling that are essential for suppression of excessive inflammation and control of the Th1
versus Th2 balance [10 – 13] (Fig. 2).
There is an important difference between PI3K- and
IRAK-M- or SOCS-1-dependent negative regulatory mechanisms. Expression of IRAK-M and SOCS-1 is inducible in
response to the first activation of TLRs and these
molecules function as negative regulators in the second
stimulation by TLR agonists [10 – 12]. Therefore, IRAK-M
and SOCS-1 contribute to the suppression of the second
challenge of TLR signaling rather than to the first one and
are thus crucial for endotoxin tolerance [8– 12]. By
contrast, PI3K is constitutively expressed in innate
immune cells and activated rapidly in response to the
first encounter to pathogens [13,21 – 23]. These results
indicate the presence of a dual-phase mechanism of
negative regulation in innate immune responses (Fig. 2).
PI3K acts as a negative regulator in the ‘early’ (or first)
phase of the innate immune response by suppressing some
of the ‘shared’ signaling pathways downstream of TLRs,
whereas IRAK-M and SOCS-1 function in the ‘late’
Opinion
TRENDS in Immunology
Effective period
Key: maintenance of proper magnitude
Magnitude of cellular response
361
Vol.24 No.7 July 2003
Tolerant period
Key: unresponsiveness
PI3K
* Imbalance of Th1 vs Th2
* Endotoxin shock
DANGEROUS ZONE!!!
Positive signals
(e.g. MAPKs and NF-κB)
IRAK-M and SOCS-1
0
Early phase
Late phase
Time of inflammation
Innate
cells
PAMPs
PRRs
Pathogen
Virus
Bacteria
Parasites
Innate immune cells
(macrophages and dendritic cells)
TRENDS in Immunology
Fig. 2. Dual-phase negative regulatory mechanism of innate immune response. Activation of PI3K is induced by the first interaction between innate immune cells and
pathogens, in which a specific PAMP triggers TLR signaling in the cells. Then, PI3K negatively regulates TLR-mediated signaling. This ‘early-phase safety system’ controlled
by PI3K confers a proper magnitude of cell activation rather than complete suppression of TLR-triggered signaling. Simultaneously, IRAK-M and SOCS-1 are induced and
have an essential role in a ‘late-phase safety system’ by inhibiting TLR signaling elicited by the second or continuous exposure of the cells to PAMPs-bearing pathogens. In
this phase, IRAK-M and SOCS-1 stringently suppress TLR-mediated signaling, resulting in the unresponsiveness of innate immune cells (endotoxin tolerance). Abbreviations: IRAK-M, interleukin-1 receptor associated kinase-M; MAPKs, mitogen-activated protein kinases; PI3K, phosphoinositide 3-kinase; PAMP, pathogen-associated
molecular pattern; PI3K, phosphoinositide 3-kinase; PRR, pattern recognition receptor; SOCS-1, suppressor of cytokine signaling-1; TLR, Toll-like receptor.
(or second) phase of the innate immune response. Thus,
the innate immune system has highly sophisticated
machinery to maintain proper magnitude of the
immune response and to protect the host from its harmful
edge (Fig. 2).
It will be of interest to know the functional relationships
of the PI3K, IRAK-M and SOCS-1 pathways in negative
signaling of TLRs. It is currently unknown how PI3K
influences the induction of IRAK-M and SOCS-1. Similarly, activation of PI3K in the presence of IRAK-M and/or
SOCS-1 should also be tested. It is possible that crosstalk
occurs between these three negative regulatory signaling
pathways in TLR signaling.
Clinical implications
IRAK-M deficient mice exhibit enhanced intestinal
inflammation, suggesting the involvement of IRAK-M in
the pathogenicity of some autoimmune diseases [10]. It is
of particular interest to examine the possible involvement
of IRAK-M in human diseases, such as inflammatory
bowel disease (IBD). In addition, it is possible that PI3K is
involved in certain diseases that are pathologically associated with the disruption of the Th1–Th2 balance [4,5,35,36].
Because dysregulation of the ‘early-phase’ safety
system by the lack of PI3K results in an imbalance of
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Th1 and Th2 responses and causes defective clearance of
intestinal parasites and effective clearance of L. major
[13,15], the PI3K-mediated machinery could be an ideal
therapeutic target (Fig. 3). Increased production of IL-12
and resultant enhancement of Th1 immune responses by
suppressing PI3K activity in DCs would be beneficial in
DC-based anti-tumor immunotherapy because the Th1
response favors effective anti-tumor immune responses
[37]. Furthermore, this strategy might be applicable to the
treatment of Th2-dominant chronic allergic diseases, such
as atopic dermatitis and asthma [38]. Specific inhibitors of
PI3K and ongoing screening of related drugs might
provide us with a proper approach [39]. In this strategy,
however, we should be careful of possible side effects,
including impingements on cell migratory capacity, endocytosis and survival [33]. Currently available PI3K
inhibitors, such as wortmannin and LY294002, are thus
unlikely to be a good choice for the clinical approach. To
avoid such side effects, it might be helpful to develop
isoform-selective PI3K inhibitors. In addition, invention
of DC-selective drug-delivery systems seems another
important approach to suppress IL-12 production in DCs
in vivo and would be helpful for therapeutic strategies
against Th1-associated symptoms, such as IBD and
other organ-specific autoimmune diseases [35]. Future
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Opinion
TRENDS in Immunology
Vol.24 No.7 July 2003
Th2-inducing factors
(e.g. IL-4, IL-6, IL-10)
IL-12
Suppression
Th2
PI3K
Target disorders
* Cancers
* Chronic allergies
(e.g. atopy,
asthma)
* Infectious diseases
(e.g. tuberculosis,
listeriosis,
HIV)
Th1
Th1 dominant immune control
Target disorders
IL-12
PI3K
Activation
Th2-inducing factors
(e.g. IL-4, IL-6, IL-10)
Th1
* Autoimmunity
(e.g. IBD,
Type 1 diabetes,
arthritis)
* GvHD
* Hepatitis
Th2
Th2 dominant immune control
* Infectious diseases
(e.g. stologyloidosis,
H. pylori)
TRENDS in Immunology
Fig. 3. PI3K as a therapeutic target in DCs. Inhibition of PI3K in DCs leads to IL-12 overexpression that might cause a skewed Th1 response. Thus, this mechanism can be
used to control the Th1– Th2 imbalance in patients with diseases caused by this disrupted equilibrium [36]. Moreover, the same strategy can be applied for DC-based cancer
immunotherapy [37]. Abbreviations: DCs, dendritic cells; GvHD, graft-versus-host disease; H. pylori, Helicobacter pylori; IBD, inflammatory bowel disease; IL-12, interleukin-12; PI3K, phosphoinositide 3-kinase.
investigations on negative regulatory mechanisms of
innate immunity might open novel clinical strategies to
cure or ameliorate miserable diseases, such as cancer,
autoimmunity and chronic allergic diseases.
Acknowledgements
We thank T. Kadowaki, Y. Terauchi and many other colleagues for fruitful
collaborations. Thanks are also due to L.K. Clayton and members of the
laboratory of S.K. for valuable discussions. S.K. is also a principal
investigator of Core Research for Evolutional Science and Technology
(CREST), Japan Science and Technology Corporation. We are supported
by a Grant-in-Aid for Creative Scientific Research (13GS0015) and a
Grant-in – Aid for Scientific Research (B) (14370116) from the Japan
Society for the Promotion of Science, a Grant-in-Aid for Scientific
Research on Priority Areas (C) (13226112, 14021110), a National Grantin-Aid for the Establishment of a High-Tech Research Center in a private
University, a grant for the Promotion of the Advancement of Education
and Research in Graduate Schools and a Scientific Frontier Research
Grant from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
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EMBO Award for communication in the life sciences 2003
Last year the European Molecular Biology Organisation launched the EMBO Award for Communication in the Life Sciences and
such was the success of this initiative, that it is being continued in 2003.
The award is intended for a life scientist who, while remaining active in research, has succeeded in making an outstanding
contribution to the communication of science to the public.
Candidates must be in active research, however, the scope of eligible activities is broad. Whether the communication is through the
media, books, public outreach projects or special initiatives, particular emphasis is placed on originality and imagination.
Furthermore, the award is specifically designed to reward the work of non-professional communicators and give encouragement to
the younger generation of life scientists, who may not be well established.
The conditions of the competition and an application form can be download from the Internet at: http://www.embo.org/
projects/scisoc/com_medal.html
The closing date for applications is 31 August 2003 and the award will be presented on 15 November during the EMBL/EMBO joint
conference on Science & Society in Heidelberg.
http://treimm.trends.com