title: Deletion of interleukin-6 in mice with the dominant negative form of transforming growth factor beta receptor II improves colitis but exacerbates autoimmune cholangitis.
abstract: The role of interleukin-6 (IL-6) in autoimmunity attracts attention because of the clinical usage of monoclonal antibodies to IL-6 receptor (IL-6R), designed to block IL-6 pathways. In autoimmune liver disease, activation of the hepatocyte IL-6/STAT3 (signal transducer and activator of transcription 3) pathway is associated with modulating pathology in acute liver failure, in liver regeneration, and in the murine model of concanavalin A-induced liver inflammation. We have reported that mice expressing a dominant negative form of transforming growth factor beta receptor II (dnTGFbetaRII) under control of the CD4 promoter develop both colitis and autoimmune cholangitis with elevated serum levels of IL-6. Based on this observation, we generated IL-6-deficient mice on a dnTGF-betaRII background (dnTGFbetaRII IL-6(-/-)) and examined for the presence of antimitochondrial antibodies, levels of cytokines, histopathology, and immunohistochemistry of liver and colon tissues. As expected, based on reports of the use of anti-IL-6R in inflammatory bowel disease, dnTGFbetaRII IL-6(-/-) mice manifest a dramatic improvement in their inflammatory bowel disease, including reduced diarrhea and significant reduction in intestinal lymphocytic infiltrates. Importantly, however, autoimmune cholangitis in dnTGFbetaRII IL-6(-/-) mice was significantly exacerbated, including elevated inflammatory cytokines, increased numbers of activated T cells, and worsening hepatic pathology.
  
  
  CONCLUSIONS
  The data from these observations emphasize that there are distinct mechanisms involved in inducing pathology in inflammatory bowel disease compared to autoimmune cholangitis. These data also suggest that patients with inflammatory bowel disease may not be the best candidates for treatment with anti-IL-6R if they have accompanying autoimmune liver disease and emphasize caution for therapeutic use of anti-IL-6R antibody.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA.
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsuda
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Guanghua
authors.initials: G
authors.lastname: Rong
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D002761:Cholangitis / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D003092:Colitis / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D018450:Disease Progression; D017353:Gene Deletion; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D018125:Receptors, Transforming Growth Factor beta