pi3k and negative regulation of tlr signaling · 2013. 9. 7. · pi3k and negative regulation of...

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


(mouse)

Signal transduction for cytokine expression [41]


(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]


(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]


(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]


(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




(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.


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




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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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

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PI3K

Suppression

Th1

IL-12

Th2

Th2-inducing factors(e.g. IL-4, IL-6, IL-10)

Th1 dominant immune control

PI3KActivation

IL-12

Th1

Th2

Th2-inducing factors(e.g. IL-4, IL-6, IL-10)

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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