Deletion of interleukin-6 in mice with the dominant negative form of transforming growth factor beta receptor II improves colitis but exacerbates autoimmune cholangitis.
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.
Zhang
Weici
W
Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA.
Tsuda
Masanobu
M
Yang
Guo-Xiang
GX
Tsuneyama
Koichi
K
Rong
Guanghua
G
Ridgway
William M
WM
Ansari
Aftab A
AA
Flavell
Richard A
RA
Coppel
Ross L
RL
Lian
Zhe-Xiong
ZX
Gershwin
M Eric
ME
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
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D018125:Receptors, Transforming Growth Factor beta