Abstract
The Toll–interleukin 1 receptor (TIR) superfamily, defined by the presence of an intracellular TIR domain, initiates innate immunity through activation of the transcription factor NF-κB, leading to the production of proinflammatory cytokines. ST2 is a member of the TIR family that does not activate NF-κB and has been suggested as an important effector molecule of T helper type 2 (TH2) responses. We show here that the membrane-bound form of ST2 negatively regulated type I interleukin 1 receptor (IL-1RI) and Toll-like receptor 4 (TLR4) but not TLR3 signaling by sequestrating the adaptors MyD88 and Mal. In contrast to wild-type mice, ST2-deficient mice failed to develop endotoxin tolerance. Thus, these results provide a molecular explanation for the function of ST2 in TH2 responses, as inhibition of TLRs promotes a TH2 response, and also identify ST2 as a key regulator of endotoxin tolerance.
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References
Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).
Dunne, A. & O'Neill, L.A. The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense. Sci. STKE 171, re3 (2003).
Fitzgerald, K.A. et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413, 78–83 (2001).
Horng, T., Barton, G.M. & Medzhitov, R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat. Immunol. 2, 835–841 (2001).
Yamamoto, M. et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling. J. Immunol. 169, 6668–6672 (2002).
Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T. & Seya, T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nat. Immunol. 4, 161–167 (2003).
Fitzgerald, K.A. et al. LPS-TLR4 signaling to IRF-3/7 and NF-κB involves the Toll adapters TRAM and TRIF. J. Exp. Med. 198, 1043–1055 (2003).
Oshiumi, H. et al. TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-β. J. Biol. Chem. 278, 49751–49762 (2003).
O'Neill, L.A. Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr. Top. Microbiol. Immunol. 270, 47–61 (2002).
Horng, T., Barton, G.M., Flavell, R.A. & Medzhitov, R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420, 329–333 (2002).
Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301, 640–643 (2003).
Wald, D. et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat. Immunol. 4, 920–927 (2003).
Sweet, M.J. et al. A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression. J. Immunol. 166, 6633–6639 (2001).
Klemenz, R., Hoffmann, S. & Werenskiold, A.K. Serum- and oncoprotein-mediated induction of a gene with sequence similarity to the gene encoding carcinoembryonic antigen. Proc. Natl. Acad. Sci. USA 86, 5708–5712 (1989).
Tominaga, S. A putative protein of a growth specific cDNA from BALB/c-3T3 cells is highly similar to the extracellular portion of mouse interleukin 1 receptor. FEBS Lett. 258, 301–304 (1989).
Werenskiold, A.K., Hoffmann, S. & Klemenz, R. Induction of a mitogen-responsive gene after expression of the Ha-ras oncogene in NIH 3T3 fibroblasts. Mol. Cell. Biol. 9, 5207–5214 (1989).
Moritz, D.R., Rodewald, H.R., Gheyselinck, J. & Klemenz, R. The IL-1 receptor-related T1 antigen is expressed on immature and mature mast cells and on fetal blood mast cell progenitors. J. Immunol. 161, 4866–4874 (1998).
Xu, D. et al. Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells. J. Exp. Med. 187, 787–794 (1998).
Coyle, A.J. et al. Crucial role of the interleukin 1 receptor family member ST2 in T helper cell type 2-mediated lung mucosal immune responses. J. Exp. Med. 190, 895–902 (1999).
Brint, E.K. et al. Characterization of signaling pathways activated by the interleukin 1 (IL-1) receptor homologue ST2. A role for Jun N-terminal kinase in IL-4 induction. J. Biol. Chem. 277, 49205–49211 (2002).
Townsend, M.J., Fallon, P.G., Matthews, D.J., Jolin, H.E. & McKenzie, A.N. ST2-deficient mice demonstrate the importance of ST2 in developing primary T helper cell type 2 responses. J. Exp. Med. 191, 1069–1076 (2000).
Muzio, M., Ni, J., Feng, P. & Dixit, V.M. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278, 1612–1615 (1997).
Wesche, H., Henzel, W.J., Shillinglaw, W., Li, S. & Cao, Z. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7, 837–847 (1997).
Yamamoto, M. et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324–329 (2002).
Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743–748 (2003).
Dinarello, C.A. The biological properties of interleukin-1. Eur. Cytokine Netw. 5, 517–531 (1994).
O'Neill, L.A. & Dinarello, C.A. The IL-1 receptor/Toll-like receptor superfamily: crucial receptors for inflammation and host defense. Immunol. Today 21, 206–209 (2000).
Burns, K. et al. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J. Exp. Med. 197, 263–268 (2003).
Kobayashi, K. et al. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110, 191–202 (2002).
Kinjyo, I. et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17, 583–591 (2002).
Greisman, S.E., Hornick, R.B., Wagner, H.N., Jr., Woodward, W.E. & Woodward, T.E. The role of endotoxin during typhoid fever and tularemia in man. IV. The integrity of the endotoxin tolerance mechanisms during infection. J. Clin. Invest. 48, 613–629 (1969).
Schnare, M. et al. Toll-like receptors control activation of adaptive immune responses. Nat. Immunol. 2, 947–950 (2001).
Muraille, E. et al. Genetically resistant mice lacking MyD88-adapter protein display a high susceptibility to Leishmania major infection associated with a polarized Th2 response. J. Immunol. 170, 4237–4241 (2003).
Lohning, M. et al. ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. Proc. Natl. Acad. Sci. USA 95, 6930–6935 (1998).
Janssens, S., Burns, K., Vercammen, E., Tschopp, J. & Beyaert, R. MyD88(S), a splice variant of MyD88, differentially modulates NF-κB- and AP-1-dependent gene expression. FEBS Lett. 548, 103–107 (2003).
Saccani, S., Polentarutti, N., Penton-Rol, G., Sims, J.E. & Mantovani, A. Divergent effects of LPS on expression of IL-1 receptor family members in mononuclear phagocytes in vitro and in vivo . Cytokine 10, 773–780 (1998).
McGuirk, P., McCann, C. & Mills, K.H. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis . J. Exp. Med. 195, 221–231 (2002).
Guidelines for the welfare of animals in rodent protection tests. A report from the Rodent Protection Test Working Party. Lab Anim. 28, 13–18 (1994).
Osborn, L., Kunkel, S. & Nabel, G.J. Tumor necrosis factor α and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor κB. Proc. Natl. Acad. Sci. USA 86, 2336–2340 (1989).
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Supported by Science Foundation Ireland, The Wellcome Trust, The Medical Research Council, UK, and the European Commission.
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Brint, E., Xu, D., Liu, H. et al. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol 5, 373–379 (2004). https://doi.org/10.1038/ni1050
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DOI: https://doi.org/10.1038/ni1050
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