A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression.
ST2/ST2L, a member of the IL-1R gene family, is expressed by fibroblasts, mast cells, and Th2, but not Th1, cells. It exists in both membrane-bound (ST2L) and soluble forms (ST2). Although ST2L has immunoregulatory properties, its ligand, cellular targets, and mode of action remain unclear. Using a soluble ST2-human IgG fusion protein, we demonstrated that ST2 bound to primary bone marrow-derived macrophages (BMM) and that this binding was enhanced by treatment with LPS. The sST2 treatment of BMMs inhibited production of the LPS-induced proinflammatory cytokines IL-6, IL-12, and TNF-alpha but did not alter IL-10 or NO production. Treatment of BMMs with sST2 down-regulated expression of Toll-like receptors-4 and -1 but induced nuclear translocation of NF-kappaB. Administration of sST2 in vivo after LPS challenge significantly reduced LPS-mediated mortality and serum levels of IL-6, IL-12, and TNF-alpha. Conversely, blockade of endogenous ST2 through administration of anti-ST2 Ab exacerbated the toxic effects of LPS. Thus, ST2 has anti-inflammatory properties that act directly on macrophages. We demonstrate here a novel regulatory pathway for LPS-induced shock via the ST2-Toll-like receptor 4 route. This may be of considerable therapeutic potential for reducing the severity and pathology of inflammatory diseases.
Sweet
M J
MJ
Department of Immunology and Bacteriology, University of Glasgow, Glasgow, G11 6NT, United Kingdom.
Leung
B P
BP
Kang
D
D
Sogaard
M
M
Schulz
K
K
Trajkovic
V
V
Campbell
C C
CC
Xu
D
D
Liew
F Y
FY
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D029721:Drosophila Proteins; D007106:Immune Sera / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011506:Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D018123:Receptors, Interleukin; D012772:Shock, Septic / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control; D015398:Signal Transduction / Q000276:immunology*; D012995:Solubility; D016019:Survival Analysis; D051193:Toll-Like Receptors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D029721:Drosophila Proteins; C486189:Il1rl1 protein, mouse; D007106:Immune Sera; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; D011506:Proteins; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D051193:Toll-Like Receptors