PI3K and negative regulation of TLRsignalingTaro 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 con-
tinuous exposure to stimulation, PI3K functions at the
early phase of TLR signaling and modulates the magni-
tude 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-likereceptors (TLRs) that recognize a variety of microbialproducts collectively termed pathogen-associated molecu-lar patterns (PAMPs) [1–3]. Stimulation through TLRs byPAMPs, such as lipopolysaccharide (LPS) (endotoxin),triggers production of various cytokines, including inter-leukin-12 (IL-12), which is a crucial inducer of Th1responses [4,5]. The resultant inflammatory response isessential for the eradication of infectious microorganisms.However, excessive and prolonged activation of innateimmunity is harmful to the host and, in some cases, evenfatal, owing to severe tissue damage and circulatoryfailure [1]. To prevent such an undesirable outcome, theinnate immune system should have a gate-keeping systemthat ensures a response with an appropriate magnitude topathogens and/or avoids responses to multiple waves ofpathogenic stimuli. Endotoxin tolerance is one suchmechanism to avoid sustained stimuli: continuousexposure to sublethal doses of endotoxin reduces febrileresponses and the host becomes resistant to subsequentchallenges with endotoxin at a lethal dose to untreatedhosts [6,7].
The hosts are able to achieve endotoxin tolerancethrough multiple processes, including downregulation ofthe LPS receptor [TLR4–MD2 (myeloid differentiation 2)complex] [8] and limited activation of NF-kB [9]. Therecent discovery of IL-1 associated kinase-M (IRAK-M),which is inducible on TLR activation, has revealed anegative regulatory mechanism for TLR signaling [10]. In
addition, suppressor of cytokine signaling-1 (SOCS-1) is anadditional inducible negative regulator of TLR signaling,although its induction occurs only through TLR4 [11,12].These findings thus present potential new molecularmechanisms for tolerance in innate immune responses.
Studies on the role of phosphoinositide 3-kinases(PI3Ks) in innate immunity have also raised a possiblesafety system to control the magnitude of cellularresponses to pathogens [13,14]. This system differs fromthe described tolerance systems, in that PI3Ks negativelyregulate TLR signaling at an earlier phase and function atthe first encounter to pathogens. In this Opinion, wediscuss these gate-keeping mechanisms in innate immu-nity and the future direction of studies, including possibletherapeutic approaches using manipulation of suchnegative feedback regulatory mechanisms in innateimmune responses.
PI3K-mediated negative feedback regulation of IL-12
production
The amount of IL-12 produced by stimulation throughTLRs is crucial in the balance between Th1 and Th2responses [4,5]. Mice lacking the p85a regulatory subunitof class IA PI3K (PI3K2/2 mice) show impaired immunityagainst the intestinal nematode, Strongyloides venezue-lensis, probably as a result of an impaired Th2 response[15]. Furthermore, PI3K2/2 mice on a BALB/c backgrounddemonstrate enhanced Th1 responses and are resistant toLeishmania major infection, unlike wild-type mice [13].These observations indicate that class IA PI3K is import-ant in the Th1 versus Th2 balance in vivo and controlsinduction of the Th2 response and/or suppression of theTh1 response. In fact, splenic and bone marrow-deriveddendritic cells (DCs) from PI3K2/2 mice produce moreIL-12 than wild-type DCs [13]. Furthermore, wortmannin,a specific inhibitor of PI3Ks, also increased IL-12 synthesisby wild-type DCs in vitro [13]. Thus, overproduction ofIL-12 by DCs is probably the main cause of the skewed Th1response in PI3K2/2 mice. These observations indicatethat PI3K has a crucial negative regulatory role duringinduction of the Th1 immune response by suppressing theproduction of IL-12 by DCs. Although individual PI3Kisoforms exhibit non-redundant specific functions [16–20]and in vivo observations are limited to the role of class IA
PI3K, pharmacological experiments raised a possiblecontribution of other class of PI3Ks in the regulation ofIL-12 production.Corresponding author: Shigeo Koyasu ([email protected]).
Opinion TRENDS in Immunology Vol.24 No.7 July 2003358
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Mechanism of PI3K-mediated suppression of IL-12
production
Notably, PI3Ks are activated in DCs by many distinctstimuli, including LPS, peptidoglycan, CpG-oligodeoxy-nucleotide (CpG-ODN), CD40L and RANKL (receptoractivator of NF-kB ligand), all of which induce IL-12production [13,21–25] (Table 1). TLRs thus simul-taneously mediate both positive and negative regulatorysignaling pathways for IL-12 production in DCs.
Signal transduction pathways that activate PI3Kdownstream of TLRs are not completely characterizedbut are classified into at least two pathways, namely‘shared’ and ‘specific’ pathways [2,3,26]. Although acti-vation of PI3K downstream of TLR2 is mediated in aRac1-dependent manner [22], it is unclear if such aRac-1-dependent signaling cascade is shared by allmembers of the TLR family. Nonetheless, PI3K is activatedafter 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 adaptorprotein (TIRAP) [also known as MyD88-adaptor-like(MAL)] and Toll–IL-1 receptor domain-containing adaptorinducing IFN-b [TRIF, also known as TIR-containingadaptor molecule-1 (TICAM-1)] are involved in specificpathways [26]. In TLR4 signaling, TAK1 (transforminggrowth 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 inresponse to LPS has been reported, demonstrating theimportance of such ‘shared’ signaling in the PI3K pathway[29]. However, there is little information on the specificityof individual PI3K isoform to TLRs.
In DCs, PI3K seems to block the p38 activationpathway. Inhibition of PI3K results in an increase in theactivity of p38 mitogen-activated protein kinase (MAPK)that is essential for transcriptional activation of both theIL-12 p35 and p40 genes [13,30], implying that directinhibition of p38 MAPK by PI3K signaling contributes tothe negative regulatory mechanism. Although it has notbeen shown how PI3K suppresses the p38 pathway, recentreports provide us with some hints (Fig. 1). Proteinkinase B (PKB)-mediated phosphorylation of apoptosissignal-regulating kinase 1 (ASK1), one of the MAPKkinase kinases (MAPKK-Ks), blocks ASK1 kinase activity,leading to suppression of MAPK kinase 3 (MKK3) orMKK6, upstream regulators of p38 [31]. Moreover, PKBblocks kinase activity of MEKK3, another MAPKK-Kupstream of p38 [32]. Because activation of PKB ispositively regulated by PI3K [33], inhibition of PI3K, orlack of PI3K, upregulates p38 activity in DCs [13].Consistent with the observation in DCs, the PI3K–PKBpathway in monocytes also suppresses both MAPKs andNF-kB cascades in response to LPS, resulting in decreasedproduction of TNF-a [14]. Because PI3K suppresses p38 inDCs [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) Signal transduction for cytokine expression [40] Proinflammatory
Monocytic cell line (THP-1) (human) Signal transduction for NF-kB activation [22]
Macrophage cell line (RAW264.7)
(mouse)
Signal transduction for cytokine expression [41]
Primary BM-derived and splenic DCs
(mouse)
Suppression of IL-12 production [13] Anti-inflammatory
TLR4 Primary monocyte-derived DCs (human) Signal transduction for cytokine expression [40] Proinflammatory
Macrophage cell line (RAW264.7)
(mouse)
Signal transduction for cytokine expression [41]
Primary BM-derived and splenic DCs
(mouse)
Inhibition of IL-12 production by p38
suppression
[13]
Primary alveolar macrophage (human) Suppression of PGE2 by negative regulation of
COX2 mRNA stability
[42] Anti-inflammatory
Monocyte cell line (THP-1) (human) Inhibition of TNF-a and TF production by
suppression of NF-kB and MAPKs
[14]
Macrophage cell line (RAW264.7)
(mouse)
Negative regulation of NO production by
suppression of NOS2 induction
[43]
Primary peritoneal macrophage (mouse) Negative regulation of NO by suppression of
NOS2 induction and inhibition of
TNF-a Production
[44]
Macrophage cell line (RAW264.7)
(mouse)
Suppression of TNF-a and NO production in
response to second activation by LPS
(endotoxin tolerance?)
[45]
TLR9 Primary BM-derived DCs (mouse) Signal transduction for IL-12 production by
induction of CpG-ODN internalization
[46] Proinflammatory
Primary splenic DCs (mouse) Signal transduction for IL-12 production [47]
Primary peritoneal macrophage (mouse) Induction of chemotaxis in response to CpG-ODN [48]
Primary BM-derived and splenic DCs
(mouse)
Suppression of IL-12 production (observed in
gene targeting of p85 subunit of class IA PI3K)
[13] Anti-inflammatory
aAbbreviations: 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.
Opinion TRENDS in Immunology Vol.24 No.7 July 2003 359
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signaling in innate immunity might not be restricted toIL-12 production (Fig. 1).
There are several reports demonstrating a proinflam-matory role for PI3K, such as positive regulation of NF-kBtransactivation [22,34] (Table 1). NF-kB transactivationby the PI3K cascade in TLR2-mediated signaling isindependent of IkBa (inhibitor of NF-kBa) degradationand triggered by PI3K-pathway-mediated p65 phosphoryl-ation [22,34]. Because NF-kB activation is required for thetranscription of both IL-12 p35 and p40 [4,5], hyper-expression of IL-12 by PI3K inhibition seems inconsistentwith such reports. According to Guha and Mackman [14],however, inhibition of PI3K augments the phosphorylationand degradation of IkBa, resulting in nuclear localizationof NF-kB in monocytes. Such qualitative differences in theactivation pathways of NF-kB might account for thedistinct effects of PI3K. Functional relationships betweenthese pathways downstream of TLRs should be examined.
Negative regulation of innate immunity and Th1 reaction
The recent discoveries of IRAK-M- and SOCS-1-dependentnegative regulatory mechanisms in TLR-signaling path-ways suggest distinct types of safety mechanisms forcontrolling inflammatory responses because IRAK-M-and SOCS-1-deficient macrophages produce enhanced
amounts of inflammatory cytokines, including IL-12[10–12]. Although SOCS-1-dependent negative regulationseems specific for TLR4 signaling [11,12], PI3K, IRAK-Mand SOCS-1 probably contribute to negative signalingcascades in TLR signaling that are essential for suppres-sion of excessive inflammation and control of the Th1versus Th2 balance [10–13] (Fig. 2).
There is an important difference between PI3K- andIRAK-M- or SOCS-1-dependent negative regulatory mech-anisms. Expression of IRAK-M and SOCS-1 is inducible inresponse to the first activation of TLRs and thesemolecules function as negative regulators in the secondstimulation by TLR agonists [10–12]. Therefore, IRAK-Mand SOCS-1 contribute to the suppression of the secondchallenge of TLR signaling rather than to the first one andare thus crucial for endotoxin tolerance [8–12]. Bycontrast, PI3K is constitutively expressed in innateimmune cells and activated rapidly in response to thefirst encounter to pathogens [13,21–23]. These resultsindicate the presence of a dual-phase mechanism ofnegative 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 someof the ‘shared’ signaling pathways downstream of TLRs,whereas IRAK-M and SOCS-1 function in the ‘late’
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, phosphoinositide-
dependent 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.
TRENDS in Immunology
PIP2
TLR2/4
MKK3/6
p38
Inflammatory cytokine gene expression
MKK4/7
JNK NF-κB
MKK1/2
PIP3
PDK
MAP3K
Rac1
PKB
IKKβ
TOLLIP
IRAK
Suppression
PI3K
TRAF6
ERK
pIRAKTAK1
MyD88
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(or second) phase of the innate immune response. Thus,the innate immune system has highly sophisticatedmachinery to maintain proper magnitude of theimmune response and to protect the host from its harmfuledge (Fig. 2).
It will be of interest to know the functional relationshipsof the PI3K, IRAK-M and SOCS-1 pathways in negativesignaling of TLRs. It is currently unknown how PI3Kinfluences the induction of IRAK-M and SOCS-1. Simi-larly, activation of PI3K in the presence of IRAK-M and/orSOCS-1 should also be tested. It is possible that crosstalkoccurs between these three negative regulatory signalingpathways in TLR signaling.
Clinical implications
IRAK-M deficient mice exhibit enhanced intestinalinflammation, suggesting the involvement of IRAK-M inthe pathogenicity of some autoimmune diseases [10]. It isof particular interest to examine the possible involvementof IRAK-M in human diseases, such as inflammatorybowel disease (IBD). In addition, it is possible that PI3K isinvolved in certain diseases that are pathologically asso-ciated with the disruption of the Th1–Th2 balance [4,5,35,36].
Because dysregulation of the ‘early-phase’ safetysystem by the lack of PI3K results in an imbalance of
Th1 and Th2 responses and causes defective clearance ofintestinal parasites and effective clearance of L. major[13,15], the PI3K-mediated machinery could be an idealtherapeutic target (Fig. 3). Increased production of IL-12and resultant enhancement of Th1 immune responses bysuppressing PI3K activity in DCs would be beneficial inDC-based anti-tumor immunotherapy because the Th1response favors effective anti-tumor immune responses[37]. Furthermore, this strategy might be applicable to thetreatment of Th2-dominant chronic allergic diseases, suchas atopic dermatitis and asthma [38]. Specific inhibitors ofPI3K and ongoing screening of related drugs mightprovide us with a proper approach [39]. In this strategy,however, we should be careful of possible side effects,including impingements on cell migratory capacity, endo-cytosis and survival [33]. Currently available PI3Kinhibitors, such as wortmannin and LY294002, are thusunlikely to be a good choice for the clinical approach. Toavoid such side effects, it might be helpful to developisoform-selective PI3K inhibitors. In addition, inventionof DC-selective drug-delivery systems seems anotherimportant approach to suppress IL-12 production in DCsin vivo and would be helpful for therapeutic strategiesagainst Th1-associated symptoms, such as IBD andother organ-specific autoimmune diseases [35]. Future
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). Abbrevi-
ations: 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.
TRENDS in Immunology
Mag
nitu
de o
f cel
lula
r re
spon
se
Positive signals(e.g. MAPKs and NF-κB)
PI3K
Time of inflammation
Early phase Late phase
IRAK-M and SOCS-1
0
Effective periodKey: maintenance of proper magnitude
DANGEROUS ZONE!!!
* Imbalance of Th1 vs Th2
Parasites
Virus
Bacteria
PRRs
PAMPs
Pathogen
Innatecells
Innate immune cells(macrophages and dendritic cells)
* Endotoxin shock
Tolerant periodKey: unresponsiveness
Opinion TRENDS in Immunology Vol.24 No.7 July 2003 361
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investigations on negative regulatory mechanisms ofinnate immunity might open novel clinical strategies tocure or ameliorate miserable diseases, such as cancer,autoimmunity and chronic allergic diseases.
AcknowledgementsWe thank T. Kadowaki, Y. Terauchi and many other colleagues for fruitfulcollaborations. Thanks are also due to L.K. Clayton and members of thelaboratory of S.K. for valuable discussions. S.K. is also a principalinvestigator of Core Research for Evolutional Science and Technology(CREST), Japan Science and Technology Corporation. We are supportedby a Grant-in-Aid for Creative Scientific Research (13GS0015) and aGrant-in–Aid for Scientific Research (B) (14370116) from the JapanSociety for the Promotion of Science, a Grant-in-Aid for ScientificResearch on Priority Areas (C) (13226112, 14021110), a National Grant-in-Aid for the Establishment of a High-Tech Research Center in a privateUniversity, a grant for the Promotion of the Advancement of Educationand Research in Graduate Schools and a Scientific Frontier ResearchGrant from the Ministry of Education, Culture, Sports, Science andTechnology, Japan.
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TRENDS in Immunology
PI3K
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PI3KActivation
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Th2 dominant immune control
Target disorders
Target disorders
* Cancers
* Chronic allergies (e.g. atopy, asthma)
* Infectious diseases (e.g. tuberculosis, listeriosis, HIV)
* Autoimmunity (e.g. IBD, Type 1 diabetes, arthritis)
* GvHD
* Hepatitis
* Infectious diseases (e.g. stologyloidosis, H. pylori)
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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.
Opinion TRENDS in Immunology Vol.24 No.7 July 2003 363
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