A novel negative regulator for IL-1 receptor and Toll-like receptor 4.
The Toll-IL-1 receptor (TIR) superfamily, defined by the presence of an intracellular TIR domain, initiates innate immunity via NF-kappaB activation, leading to production of proinflammatory cytokines. ST2 is a member of the TIR family that does not activate NF-kappaB and has been suggested as an important effector molecule of type 2 T helper cell responses. We have recently demonstrated that the membrane bound form of ST2 (ST2L) negatively regulated IL-1RI and 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, ST2 suppresses IL-1R and TLR4 signaling via MyD88- and Mal-dependent pathways and modulates innate immunity. The results provide a molecular explanation for the role of ST2 in T(H)2 responses since inhibition of TLRs will promote a T(H)2 response and also identify ST2 as a key regulator of endotoxin tolerance.
Liew
Foo Y
FY
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow G11 6NT, UK. fyl1h@clinmed.gla.ac.uk
Liu
Haiying
H
Xu
Damo
D
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D004731:Endotoxins / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008070:Lipopolysaccharides / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D009185:Myelin Proteins / Q000378:metabolism; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; D011510:Proteolipids / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D004731:Endotoxins; C486189:Il1rl1 protein, mouse; D007375:Interleukin-1; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008070:Lipopolysaccharides; C569027:Mal protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C507780:Myd88 protein, mouse; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; D011510:Proteolipids; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors