Reviews and Monographs

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1 Reviews and Monographs Progress in Biochemistry and Biophysics 2009, 36(12): 1516~1522 wwwpibbaccn * Toll ** ( ) Toll (Toll-like receptors TLRs) TLRs TLRs TLRs TLRs Toll (TLRs) Q93 DOI: /SPJ Toll (TLRs) IRAK-4 6 (TNFRassociated factor 6, TRAF-6) TLRs 12 [1] (mitogen activated protein kinase MAPK) IκB TLRs (IκB kinase IκK ) κb (nuclear factor κb NF-κB ) TLRs TIR (pathogen-associated molecular patterns, PAMPs) [2] factor 88 MyD88) MyD88- PAMPs (MyD88-adaptor like Mal) TIR TLRs PAMPs β (TIR domain-containing TLRs adaptor inducing interferon β TRIF) TRIF TLRs (TRIF-related adaptor molecule TRAM ) SARM (sterile α and armadillo motif-containing protein) [4] TLRs TLRs MyD88 TLR3 TLRs [3] TLRs MyD88 TIR TLRs IRAK-4 IRAK-4 1 TLRs IRAK-1 TRAF6 TLR (TLR3 ) (E3) (E2) ( 1) IKK-γ TLRs Toll/IL-1 (Toll/IL-1 receptor homologous region TIR)TIR 1 (IL-1R associated kinase IRAK) IRAK -1 88(myeloid differentiation * ( ) ** Tel: , Fax: daishu@publicbtanetcn

2 2009; 36 (12) Toll 1517 TGF-β (TGF-β activated kinase 1 TAK1) TAK1 (TAK1 binding protein TAB1 TAB2 TAB3) TAK1 IKK-β NF-κB LPS TLR4 NF-κB TLRs TLRs Mal TRAM TRIF TLRs [5] TRIF (LPS) TLRs TLR4 Poly(I C) TLR3 TRAM TLR4 TLRs TLRs ( 1) 2 mrna TLR4 TLRs(sTLRs) 3 TLRs (phosphatidylinositol 3 kinase PI3K) TLRs stlr4 TLR4 stlr4 (LPS) NF-κB

3 1518 Prog Biochem Biophys 2009; 36 (12) 32 2 (myeloid TLRs differentiation protein 2 MD2) TLR4 TLR4 LPS MD2 105(radioprotective 105 RP105) TLR4 stlr4 TLR4 MD2 TIR stlr4 HEK293 RP105 TLR2 (stlr2) [6] 6(growth arrest- RP105 specific gene 6 Gas6) TLRs Divanovic [11] RP105 TLR4/ Gas6 K MD2 LPS TLR4/MD2 75 ku (Glu ) 4 TLR4 (EGF ) (G IL-1 ( single S(protein S) 46% immunoglobulin IL-1 related protein SIGIRR ) TAM TIR-8 [12] TIR TLRs SIGIRR [7] TLRs 3 TLR DCs SIGIRR IL-1 31 TLRs SIGIRR Poly(I C) SIGIRR 2(suppressor of tumorigenicity [8] ST2) IRAK TRAF TLR ST2 ST2L IRAK TRAF sst2 ST2L TIR ( 3 33 (RTK) [13] )sst2 ST2L TAM RTK 3 Tyo3 [8] C 9 IL-1 LPS Axl Mer (CpG) TLRs ST2L sst2 [14] LPS(TLR4 ) TAM Poly(I C) (DCs) ST2L MyD88 6 ST2L MyD88 (IL-6) α(tnf-α) Mal MyD88 Mal ST2L (TIR box2 ) Mal MyD88 NF-κB LPS ) DCs LPS Poly sst2 TLR1 (I C) CpG TLR4 sst2 TAM Gas6 THP-1 IL-6 IL-1β (type interferon receptor IFNR1) TNF-α [9, 10] ST2 TLRs IFNR1 STAT1 TLR4 LPS (DCs) LPS SIGIRR IL-18 NF-κB SIGIRR NF-κB MyD88 IL-1 SIGIRR IL-1 Poly(I C)(TLR3 ) CpG(TLR9 ) DCs Gas6(TAM STAT1 1(suppressor of cytokine signaling 1 SOCS-1) SOCS-3

4 2009; 36 (12) Toll 1519 SOCS-1 Mal SOCS-3 LPS TRAF-6 TLRs SOCS-1 SOCS-1 -/- LPS 34 (tumor SOCS-1 LPS necrosis factor-related apoptosis-inducing ligand NF-κBLPS SOCS-1 -/- receptor TRAILR) TIR JNK IκB p38 SOCS-1 TNF TLR TLRs Mansell [17] TRAILR SOCS-1 Mal TLR2 TLR4 TLR2 TLR3 TLR4 SOCS-1 Mal P65 NF-κB TRAILR Mal SOCS-1 TLR4 IL-12 [15] SOCS-1 TLR3 [18] IκB-α NF-κB 1(prolylisomerase 1 Pin-1) TRAILR TLR TLR IκB-α IκB-α NF-κB IRF IRF-3 NF-κB TLRs [15] IFN-β Pin-1 TLR 4 Pin-1 TLRs p65 NF-κB Pin SOCS-1 p65 41 Pin-1 p65 SOCS-1 NF-κB TLRs Pin-1 SOCS-1 p65 (Triad3A) E3 42 TLRs Triad3A TIR Triad3A TLRs TLR4 TLR9 TLR2 TLR3 TLR A20 Triad3A TLR4 TLR9 TLR2 TNF NF-κB Triad3A TIR RIP-1 TRIF Mal [16] RIP1 TLRs Triad3A E3 RIP1 LPS CpG NO [19] Pin-1 dsrna Pin-1 A20 A20 SOCS Src TLR2 TLR3 TLR9 SH-2 C A20 SOCS (SOCS box)socs 8 TRAF-6 SOCS-1 SOCS-3 NF-κB [20]

5 1520 Prog Biochem Biophys 2009; 36 (12) CYLD(cyclindomatosis) NF-κB Yoshida [21] IRAK-2 IRAK-M IRAK CYLD TLR2 / IRAK-2 CYLD sirna TLR2 IRAK-M / HEK PGN MALP-2 IRAK-M -/- Pam3CSK-4(TLR2 ) LPS NF-κB TNF-α IL-1β IL-8 IRAK-M IRAK-1/ TLR2 CYLD IRAK-4 MyD88 IRAK-1 TRAF-6 TRAF-7 NF-κB [21] P38 43 IRAK-2b IRAK-2c IRAK-2dIRAK-2a IRAK-2b NF-κB TLRs SARM IRAK-2c IRAK-2d N DD MyD88 NF-κB NF-κB sterile α (SAM) IRAK-2 armadillo TIR TLRs DD IRAK-2c NLP-29 NLP-3143 IRAK-2d SARM 3(activating transcript factor 3 RNAi SARM ATF-3) CREB/ATF Poly(I C) LPS p53 TNF [22] SARM TRIF IL-6 IL bp TLR3 TLR4 SARM N NF-κB ATF-3 LPS SARM LPS ATF-3 -/- [22] LPS TLRs IL-6 IL-12 [26] ATF-3 SARM LPS LPS IL-6 IL-12 ATF-3 SARM TRIF SARM TRIF NF-κB DNA LPS ATF-3 TLR4 [23] TRIF MyD88 TLRs(TLR3 ) N (death domain, DD) C ( DC specific intercellular adhesion molecule 3 MyD88(MyD88s) grabbing nonintegrin DC-SIGN) LPS MyD88s NF-κB TLRs DC-SIGN C IRAK-4 IRAK-1 DC-SIGN TNF NF-κB MyD88s ManLAM TLR4 MyD88 IRAK-1 ManLAM TLR4 IRAK-1 NF-κB DC-SIGN LPS MyD88s MyD88s MyD88 IRAK-1 44 [25] TRAF-6 IRAK-2 4 IRAK-2a ATF-3 TLRs 3 / Raf-1 [27] MyD88 NF-κB p65 IRAK-4 IL-10 p65 Raf-1 IRAK-4 Raf-1 ManLAM [24] IRAK-1 NF-κB TLR IL-10mRNA

6 2009; 36 (12) Toll 1521 Raf-1 NF-κB TLRs Src 2 2(Src homology 2-containing protein tyrosine phosphatase-2, SHP-2) INF-β(TLR3 TLR4 ) SHP-2 JAK STAT SHP-2 sirna LPS Poly(I C) IFN-β [27] Poly(I C) LPS 827 SHP-2 -/- TNF-α IL-6 SHP-2 TRIF SHP-2 -/ - TLR2 TLR7 TLR9 TNF-a IL-6 (5): 353~364 Poly(I C) IRF-3 SHP-2 [28] IRF-3 SHP-2 TBK-1(TRIF ) N TBK-1 [28] SHP-2 TLRs 44(8): 1969~1976 TLRs 30α (tripartite-motif protein 30α Trim30α) TAB2 TAB3 NF-κB TAB2 TAB3 (NH 4 Cl ) TAB2 Trim30α TAB Trim30α [29] Trim30α TLRs 5 TLRs (6): 363~368 1 Fischer M, Ehlers M Toll-like receptors in autoimmunity Ann N Y Acad Sci, 2008, 1143: 21~34 2, Toll (TLRs), 2006, 33(9): 820~827 Wang H K, Han D S Prog Biochem Biophys, 2006, 33(9): 820~ 3 Wang J, Hu Y, Deng W W, et al Negative regulation of Toll-like receptor signaling pathway Microbes Infect, 2009, 11(3): 321~327 4 O'Neill L A, Bowie A G The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling Nat Rev Immunol, 2007, 7 5 Creagh E M, O'Neill L A TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity Trends Immunol, 2006, 27(8): 352~357 6 Kuroishi T, Tanaka Y, Sakai A, et al Human parotid saliva contains soluble toll-like receptor (TLR) 2 and modulates TLR2-mediated interleukin-8 production by monocytic cells Mol Immunol, 2007, 7 Fernández-Fernández L, Bellido-Martín L, García de Frutos P Growth arrest-specific gene 6 (GAS6) An outline of its role in haemostasis and inflammation Thromb Haemost, 2008, 100 (4): 604~610 8 O'Neill L A The interleukin-1 receptor/toll-like receptor superfamily: 10 years of progress Immunol Rev, 2008, 226(1): 10~18 9 Sweet M J, Leung B P, Kang D, et al A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression J Immunol, 2001, 166(11): 6633~ 10 Takezako N, Hayakawa M, Hayakawa H, et al ST2 suppresses IL-6 production via the inhibition of IkappaB degradation induced by the LPS signal in THP-1 cells Biochem Biophys Res Commun, 2006, 341(2): 425~ Divanovic S, Trompette A, Atabani S F, et al Inhibition of TLR-4/MD-2 signaling by RP105/MD-1 J Endotoxin Res, 2005, Lech M, Kulkarni O P, Pfeiffer S, et al Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus TLRs autoantigens J Exp Med, 2008, 205(8): 1879~1888 TLRs 13 Hafizi S, Dahlb 覿 ck B Gas6 and protein S Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily FEBS J MyD , 273(23): 5231~5244 MyD88 14 Rothlin C V, Ghosh S, Zuniga E I, et al TAM receptors are pleiotropic inhibitors of the innate immune response Cell, 2007, 131(6): 1124~ Diehl G E, Yue H H, Hsieh K, et al TRAIL-R as a negative regulator of innate immune cell responses Immunity, 2004, 21(6): 877~ Fearns C, Pan Q, Mathison J C, et al Triad3A regulates MyD88

7 1522 Prog Biochem Biophys 2009; 36 (12) ubiquitination and proteasomal degradation of RIP1 following disruption of Hsp90 binding J Biol Chem, 2006, 281(45): 34592~ Mansell A, Smith R, Doyle S L, et al Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation Nat Immunol, 2006, 7(2): 148~ Pothlichet J, Chiqnard M, Si-Tahar M Cutting edge: innate immune response triggered by influenza A virus is negatively regulated by SOCS1 and SOCS3 through a RIG-I/IFNAR1-dependent pathway J Immunol, 2008, 180(4): 2034~ Saitoh T, Tun-Kyi A, Ryo A, et al Negative regulation of interferonregulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1 Nat Immunol, 2006, 7(6): 598~ Kameda H, Watanabe M, Bohqaki M, et al Inhibition of NF-kappaB signaling via tyrosine phosphorylation of Ymer Biochem Biophys Res Commun, 2009, 378(4): 744~ Yoshida H, Jono H, Kai H, et al The tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for Toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7 J Biol Chem, 2005, 280(49): 41111~ Carty M, Goodbody R, Schroder M, et al The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling Nat Immunol, 2006, 7(10): 1074~ Kenny E F, O'Neill L A Signalling adaptors used by Toll-like receptors: an update Cytokine, 2008, 43(3): 342~ Mendoza-Barberá E, Corral-Rodríguez M A, Soares-Schanoski A, et al Contribution of globular death domains and unstructured linkers to MyD88 IRAK-4 heterodimer formation: an explanation for the antagonistic activity of MyD88s Biochem Biophys Res Commun, 2009, 380(1): 183~ Nquyen T, De Nardo D, Masendycz P, et al Regulation of IRAK-1 activation by its C-terminal domain Cell Signal, 2009, 21(5): 719~ Whitmore M M, Iparraguirre A, Kubelka L, et al Negative regulation of TLR-signaling pathways by activating transcription factor-3 J Immunol, 2007, 179(6): 3622~ den Dunnen J, Gringhuis S I, Geijtenbeek T B Innate signaling by the C-type lectin DC-SIGN dictates immune responses Cancer Immunol Immunother, 2009, 58(7): 1149~ An H, Zhao W, Hou J, et al SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type interferon and proinflammatory cytokine production Immunity, 2006, 25 (6): 919~ Shi M, Deng W, Bi E, et al TRIM30 alpha negatively regulates TLR-mediated NF-kappa B activation by targeting TAB2 and TAB3 for degradation Nat Immunol, 2008, 9(4): 369~377 Negative Regulation of Toll-like Receptors Signaling Pathways * SUN Bing, HAN Dai-Shu ** (Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing , China) Abstract Toll-like receptors (TLRs) are key mediators of both innate and adaptive immunity by recognizing and eliciting responses to invading pathogens The activation of TLRs must be stringently controlled in order to avoid exaggerated expression of signaling components as well as pro-inflammatory cytokines that can devastate the host, resulting in chronic inflammatory diseases, autoimmune disorders and aid in the pathogenesis of TLR-associated diseases Therefore, it is essential that negative regulators act at multiple levels within TLR signaling cascades in order to synchronize the activation and negative regulation of signal transduction to limit potentially harmful immunological consequences A summary of the various mechanisms employed by negative regulators of TLRs signaling to ensure the appropriate modulation of both immune and inflammatory responses was provided Key words Toll-like receptors, inflammation, negative regulation, signal transduction DOI: /SPJ *This work was supported by a grant from The National Natural Science Foundation of China ( ) **Corresponding author Tel: , Fax: , daishu@publicbtanetcn Received: April 6, 2009 Accepted: July 23, 2009