Pivotal roles of interleukin-6 in transmural inflammation in murine T cell transfer colitis.
Breakdown of normal mucosal immunity is one of the major causes for inflammatory bowel disease. Interleukin (IL)-6 is a proinflammatory cytokine produced aberrantly in various types of inflammation, but its role in inflammatory bowel disease is still obscure. Hence, we analyzed the roles of IL-6 in the pathogenesis of murine T cell transfer colitis, whose histopathology resembles Crohn's disease. The transfer of CD4+CD45RBhigh T cells into severe combined immunodeficiency mice induced the infiltration of T cells and macrophages, and the gene expression of CC chemokine receptor (CCR)1, CCR2, CCR5, CXC chemokine receptor 3, their ligands, tumor necrosis factor-alpha, interferon-gamma, and IL-6 was progressively augmented as colitis developed. The incidence of transmural colitis was significantly reduced with a minimal decrease in the severity of colitis in recipients transferred with CD4+CD45RBhigh T cells derived from IL-6-deficient mice compared with those with wild-type mice. Moreover, the gene expression of several cytokines, chemokines, and matrix metalloproteinases was reduced significantly in recipients transferred with IL-6-deficient, mice-derived T cells. These observations suggested that T cell-derived IL-6 may augment the gene expression of several proinflammatory molecules, thereby causing transmural inflammation. Thus, IL-6 might be a promising target for treating transmural inflammation in Crohn's disease, which can lead to severe complications such as strictures, fissures, and fistulas.
Kitamura
Kazuya
K
Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8641, Japan. kkitamura@medf.m.kanazawa-u.ac.jp
Nakamoto
Yasunari
Y
Kaneko
Shuichi
S
Mukaida
Naofumi
N
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018925:Chemokines / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003092:Colitis / Q000276:immunology* / Q000503:physiopathology; D003424:Crohn Disease / Q000276:immunology* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics*; D017493:Leukocyte Common Antigens / Q000276:immunology; D020782:Matrix Metalloproteinases / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D019707:Receptors, Chemokine / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D018925:Chemokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D019707:Receptors, Chemokine; D017493:Leukocyte Common Antigens; D020782:Matrix Metalloproteinases