title: Aberrant accumulation of interleukin-10-secreting neutrophils in TRAF2-deficient mice.
abstract: Highly coordinated expression of inflammatory and anti-inflammatory cytokines is crucial for maintaining homeostasis of the gut that is constantly exposed to large amounts of commensal bacteria. We have previously reported that tumor necrosis factor (TNF) receptor-associated factor (Traf)2(-/-) mice spontaneously develop severe colitis and that the development of colitis largely depends on TNFα-dependent apoptosis of colonic epithelial cells. However, the detailed molecular mechanisms underlying the immunological disorders of Traf2(-/-) mice are not fully understood. Here we show that interleukin (IL)-10-secreting neutrophils accumulated in peripheral blood and bone marrow (BM) cells from Traf2(-/-) mice compared with those from wild-type mice. Treatment of Traf2(-/-) mice with neutralizing antibody against TNFα or crossing Traf2(-/-) mice with Tnfr1(-/-) mice reduced the percentages of IL-10-secreting neutrophils, suggesting that the development of IL-10-secreting neutrophils largely depended on TNFα signals. Moreover, stimulation of BM cells from wild-type mice with lipopolysaccharide and Pam3CS(K)4, a ligand for Toll-like receptor 4 and 2, respectively, induced differentiation of BM cells into IL-10-secreting neutrophils. These results suggest that the development of IL-10-secreting neutrophils is not restricted to Traf2(-/-) mice, but could be generalized to wild-type mice under certain conditions such as inflammation. Finally, combined treatment of Traf2(-/-) mice with neutralizing antibodies against TNFα and IL-10, but not each antibody alone, substantially ameliorated colitis and prolonged survival. Together, abrogation of immunosuppressive conditions mediated by IL-10-secreting neutrophils might be an alternative strategy to treat chronic inflammatory diseases at least under certain conditions.
authors.affiliation: Department of Immunology, Juntendo University School Graduate School of Medicine, Tokyo, Japan.
authors.forename: Jiang-Hu
authors.initials: JH
authors.lastname: Piao
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Nakano
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D005434:Flow Cytometry; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016019:Survival Analysis; D047992:TNF Receptor-Associated Factor 2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D055666:Lipopeptides; D008070:Lipopolysaccharides; C560312:Pam2CSK4 lipopeptide; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10