Abstract
IFN-γ is a signature Th1 cell associated cytokine critical for the inflammatory response in autoimmunity with both pro-inflammatory and potentially protective functions. IL-17A is the hallmark of T helper 17 (Th17) cell subsets, produced by γδT, CD8+ T, NK and NKT cells. We have taken advantage of our colony of IL-2Rα−/− mice that spontaneously develop both autoimmune cholangitis and inflammatory bowel disease. In this model CD8+ T cells mediate biliary ductular damage, whereas CD4+ T cells mediate induction of colon-specific autoimmunity. Importantly, IL-2Rα−/− mice have high levels of interferon γ (IFN-γ), and interleukin-17A (IL-17A). We produced unique double deletions of mice that were either IL-17A−/−IL-2Rα−/− or IFN-γ−/−IL-2Rα−/− to specifically address the precise role of these two cytokines in the natural history of autoimmune cholangitis and colitis. Of note, deletion of IL-17A in IL-2Rα−/− mice led to more severe liver inflammation, but ameliorated colitis. In contrast, there were no significant changes in the immunopathology of double knock-out IFN-γ−/− IL-2Rα−/− mice, compared to single knock-out IL-2Rα−/− mice with respect to cholangitis or colitis. Furthermore, there was a significant increase in pathogenetic CD8+ T cells in the liver of IL-17A−/−IL-2Rα−/− mice. Our data suggest that while IL-17A plays a protective role in autoimmune cholangitis, it has a pro-inflammatory role in inflammatory bowel disease. These data take on particular significance in the potential use of anti-IL-17A therapy in humans with primary biliary cirrhosis.
Highlights
Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease characterized by destruction of small bile ducts and the presence of anti-mitochondrial antibodies (AMA) [1]
IL-2Ra2/2 CD4+ T cells are the primary source of IL-17A; IL-2Ra2/2 CD8+ T cells predominantly produce interferon c (IFN-c)
CD8+ T cells from IL-2Ra2/2 mice produced a greater quantity of IFN-c compared to IL-2Ra+/2 in liver (P = 0.0159), but almost no IL-17A
Summary
Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease characterized by destruction of small bile ducts and the presence of anti-mitochondrial antibodies (AMA) [1]. We previously reported that IL-2Ra2/2 mice spontaneously develop an autoimmune biliary ductular disease, exhibiting major serological and histological characteristics of human PBC [2] as well as an inflammatory bowel disease (IBD), characterized by diarrhea and wasting [3]. Serum levels of inflammatory cytokines, including TNF-a, IL-12p40, and IL-6, increased with the age of animals. IFN-c is the signature Th1 cell associated cytokine, which plays a critical role in inflammation and autoimmune disease, with both proinflammatory and protective functions [5]. To examine in specific detail the role of IFN-c versus IL-17A in autoimmune cholangitis and colitis, we took advantage of IL17A2/2IL-2Ra2/2 and IFN-c2/2IL-2Ra2/2 mice. Our data suggests that IL-17A plays a protective role in autoimmune cholangitis but a proinflammatory role in colitis in IL-2Ra2/2 mice
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