Deletion of interleukin-6 in mice with the dominant negative form of transforming growth factor β receptor II improves colitis but exacerbates autoimmune cholangitis

Weici Zhang, Masanobu Tsuda, Guo Xiang Yang, Koichi Tsuneyama, Guanghua Rong, William M. Ridgway, Aftab A. Ansari, Richard A. Flavell, Ross L. Coppel, Zhe Xiong Lian, M. Eric Gershwin

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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 β receptor II (dnTGFβRII) 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-βRII background (dnTGFβRII 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, dnTGFβRII 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 dnTGFβRII IL-6-/- mice was significantly exacerbated, including elevated inflammatory cytokines, increased numbers of activated T cells, and worsening hepatic pathology. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)215-222
Number of pages8
JournalHepatology
Volume52
Issue number1
DOIs
StatePublished - Jul 2010

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Cholangitis
Growth Factor Receptors
Transforming Growth Factors
Colitis
Interleukin-6 Receptors
Interleukin-6
Inflammatory Bowel Diseases
Pathology
Autoimmune Diseases
Liver Diseases
Liver
Cytokines
STAT3 Transcription Factor
Liver Regeneration
Acute Liver Failure
Antibodies
Therapeutic Uses
Concanavalin A
Autoimmunity
Hepatocytes

ASJC Scopus subject areas

  • Hepatology

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Deletion of interleukin-6 in mice with the dominant negative form of transforming growth factor β receptor II improves colitis but exacerbates autoimmune cholangitis. / Zhang, Weici; Tsuda, Masanobu; Yang, Guo Xiang; Tsuneyama, Koichi; Rong, Guanghua; Ridgway, William M.; Ansari, Aftab A.; Flavell, Richard A.; Coppel, Ross L.; Lian, Zhe Xiong; Gershwin, M. Eric.

In: Hepatology, Vol. 52, No. 1, 07.2010, p. 215-222.

Research output: Contribution to journalArticle

Zhang, Weici ; Tsuda, Masanobu ; Yang, Guo Xiang ; Tsuneyama, Koichi ; Rong, Guanghua ; Ridgway, William M. ; Ansari, Aftab A. ; Flavell, Richard A. ; Coppel, Ross L. ; Lian, Zhe Xiong ; Gershwin, M. Eric. / Deletion of interleukin-6 in mice with the dominant negative form of transforming growth factor β receptor II improves colitis but exacerbates autoimmune cholangitis. In: Hepatology. 2010 ; Vol. 52, No. 1. pp. 215-222.
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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 β receptor II (dnTGFβRII) 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-βRII background (dnTGFβRII 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, dnTGFβRII 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 dnTGFβRII IL-6-/- mice was significantly exacerbated, including elevated inflammatory cytokines, increased numbers of activated T cells, and worsening hepatic pathology. Conclusion: 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.",
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AU - Rong, Guanghua

AU - Ridgway, William M.

AU - Ansari, Aftab A.

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AU - Coppel, Ross L.

AU - Lian, Zhe Xiong

AU - Gershwin, M. Eric

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AB - 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 β receptor II (dnTGFβRII) 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-βRII background (dnTGFβRII 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, dnTGFβRII 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 dnTGFβRII IL-6-/- mice was significantly exacerbated, including elevated inflammatory cytokines, increased numbers of activated T cells, and worsening hepatic pathology. Conclusion: 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.

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