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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. http://treimm.trends.com 1471-4906/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1471-4906(03)00139-X 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. http://treimm.trends.com 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 http://treimm.trends.com 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 http://treimm.trends.com 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 362 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. 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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