Original ResearchBasic and Translational—LiverInterleukin-17 Signaling in Inflammatory, Kupffer Cells, and Hepatic Stellate Cells Exacerbates Liver Fibrosis in Mice
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Cell Lines and Mice
LX-2 cell line (gift of Dr Friedman)12 and hTERT cell line13 and Collagen α1(I)-GFP mice14 were previously described. C57BL/6 mice (8 weeks old) and GFAP-Cre mice were purchased (Jackson Laboratories, Bar Harbor, ME). We obtained IL-17RA−/− mice15 (gift of Dr Kolls), IL-17A−/− mice16 (gift of Dr Iwakura), and STAT3f/f mice17 (gift of Dr Takeda) and IL-22−/− mice and IL-23−/− mice (Genentech, San Francisco, CA). All animal experiments were approved by the University of California, San Diego
Progression of Liver Fibrosis Correlates With Elevated Expression of IL-17
Expression of IL-17A and IL-17F and their cognate receptors IL-17RA and IL-17RC was examined in 2 models of liver fibrosis in mice: BDL and CCl4. We determined that mRNA levels of IL-17A, IL-17F, IL-17RA, and IL-17RC in fibrotic livers were strongly up-regulated independent of the etiology of fibrosis (Figure 1A). Development of liver fibrosis was also associated high levels of circulating IL-17A (Figure 1A). Moreover, increased expression of IL-17A was detected in livers from patients with
Discussion
Our study demonstrates that IL-17 plays a critical role in the pathogenesis of cholestatic and hepatotoxic liver fibrosis in mice. IL-17 has a strong profibrogenic effect through 2 independent mechanisms: First, IL-17 stimulates KC to express inflammatory cytokines IL-6, IL-1β, and TNF-α, as well as the major fibrogenic cytokine TGF-β1. Second, IL-17 directly stimulates HSCs to express collagen type I and promotes their activation into fibrogenic myofibroblasts via Stat3. IL-17 may serve as an
Acknowledgments
The authors thank Dr Yanagida (Kyoto University) and Karin Diggle (UCSD) for support.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by the National Institutes of Health (GM41804, AA15055, DK72237, AI077780), the American Liver Foundation (2006 Liver Scholar Research Award), Shandong Province Science and Technology Plan (2006GG2202042), and Key Project of Chinese Ministry of Science and Technology (2008ZX10002-007) IK99DK088589-01A1 and CCFA No. 2693.