title: ST2, an IL-1R family member, attenuates inflammation and lethality after intestinal ischemia and reperfusion.
abstract: Ischemia reperfusion injury is characterized by local and systemic inflammation leading to considerable mortality. Previously, we have reported that soluble T1/ST2 (sST2), a member of the IL-1 receptor gene family, inhibits LPS-induced macrophage proinflammatory cytokine production. Here, we report the therapeutic effect of sST2-Fc in a murine model of intestinal ischemia reperfusion-induced injury. Administration of sST2-Fc fusion protein i.v., 10 min before reperfusion, reduced the production of TNF-alpha dose-dependently in the intestine and in the lungs. The sST2-Fc treatment with the highest dose (100 mug) resulted in inhibited vascular permeability, neutrophilia, and hemorrhage in the intestine and the lungs compared with controls treated with normal IgG. This was associated with down-regulated tissue levels of proinflammatory cytokines, markedly reduced serum TNF-alpha levels, and increased survival of mice from the sST2-Fc-treated group after ischemia and reperfusion injury. The beneficial effect of sST2-Fc treatment was associated with elevated IL-10 production in intestine and lung. sST2-Fc was not able to prevent the inflammatory response associated with intestinal ischemia and reperfusion in IL-10-deficient mice, suggesting that sST2 exerts its anti-inflammatory effect in a IL-10-dependent manner. These results also demonstrate that sST2-Fc may provide a novel, complementary approach in treating ischemic reperfusion injury.
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Pampulha, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Caio T
authors.initials: CT
authors.lastname: Fagundes
authors.forename: Flávio A
authors.initials: FA
authors.lastname: Amaral
authors.forename: Adriano L S
authors.initials: AL
authors.lastname: Souza
authors.forename: Angélica T
authors.initials: AT
authors.lastname: Vieira
authors.forename: Damo
authors.initials: D
authors.lastname: Xu
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: Danielle G
authors.initials: DG
authors.lastname: Souza
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D007249:Inflammation; D000072179:Interleukin-1 Receptor-Like 1 Protein; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency; D007422:Intestines / Q000276:immunology / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D015996:Survival Rate; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C486189:Il1rl1 protein, mouse; D007141:Immunoglobulin Fc Fragments; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008565:Membrane Proteins; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10