Deletion of Interleukin-6 in Mice With the Dominant Negative Form of Transforming Growth Factor β 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 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. Hepatology 2010

The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17a deleted dominant negative form of transforming growth factor beta receptor type ii mice

“…It has also been suggested that IL‐23 might directly activate a subset of macrophages and dendritic cells expressing the IL‐23 receptor, resulting in the production of inflammatory mediators, such as TNF‐α, IL‐6, and IL‐1 25. Of note, using our dnTGFβRII mice model, we recently reported that depletion of IL‐6 significantly improved colitis, but exacerbated autoimmune cholangitis in the liver 31. These studies indicate that the role of IL‐6 in the pathogenesis of organ‐specific autoimmune diseases is also different between the liver and colon.…”

Therapeutic Effect of Cytotoxic T Lymphocyte Antigen 4/Immunoglobulin on a Murine Model of Primary Biliary Cirrhosis

“…At present, it is not clear whether there is a hierarchy among these molecules in terms of an ordered sequence by which these molecules act to regulate immune responses. In light of our previous studies on the role of inflammatory cytokines, such as interferon‐gamma, interleukin (IL)‐6, IL‐12, and IL‐23,51‐53 in the pathogenesis of PBC (including autoAb production and biliary cell damages), it is reasonable to assume that CTLA‐4 could influence the effect of these downstream inflammatory cytokines. However, it is clear that they do serve at different check points along the T‐cell activation pathway, and it is likely that an optimized therapeutic approach may require a combination of therapeutic inhibitors to maintain long‐term inhibition of autoimmune‐effector mechanisms54 without compromising antiviral and tumor surveillance mechanisms.…”

Modeling toxicodynamic effects of trichloroethylene on liver in mouse model of autoimmune hepatitis

“…peritoneal exudate macrophages vs Kupffer cells). Deletion of IL-6 in mice deficient in TGF-β receptor II improved colitis but exacerbated autoimmune cholangitis in association with increased numbers of activated T cells (Zhang et al ., 2010). …”

“…Disruption of IL-6, or its receptors IL-6R or Gp130, has been shown to promote liver inflammation and/or mortality following partial hepatectomy (Wuestefeld et al , 2003), ethanol-induced liver disease (Gao, 2012), carbon tetrachloride-induced liver necrosis (Bansal et al , 2005), obesity-associated insulin resistance (Wunderlich et al , 2010), autoimmune cholangitis (Zhang et al , 2010), and Con A-induced hepatitis (Lutz et al , 2012). Thus, IL-6 appears to prevent immunological liver injury.…”