Gastroenterology

Gastroenterology

Volume 143, Issue 3, September 2012, Pages 765-776.e3
Gastroenterology

Original Research
Basic and Translational—Liver
Interleukin-17 Signaling in Inflammatory, Kupffer Cells, and Hepatic Stellate Cells Exacerbates Liver Fibrosis in Mice

https://doi.org/10.1053/j.gastro.2012.05.049Get rights and content

Background & Aims

Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice.

Methods

Using cholestatic and hepatotoxic models of liver injury, we compared the development of liver fibrosis in wild-type mice with that of IL-17RA−/− mice and of bone marrow chimeric mice devoid of IL-17 signaling in immune and Kupffer cells (IL-17RA−/− to wild-type and IL-17A−/− to wild-type mice) or liver resident cells (wild-type to IL-17RA−/− mice).

Results

In response to liver injury, levels of Il-17A and its receptor increased. IL-17A increased appeared to promote fibrosis by activating inflammatory and liver resident cells. IL-17 signaling facilitated production of IL-6, IL-1, and tumor necrosis factor-α by inflammatory cells and increased the expression of transforming growth factor-1, a fibrogenic cytokine. IL-17 directly induced production of collagen type I in hepatic stellate cells by activating the signal transducer and activator of transcription 3 (Stat3) signaling pathway. Mice devoid of Stat3 signaling in hepatic stellate cells (GFAPStat3−/− mice) were less susceptible to fibrosis. Furthermore, deletion of IL-23 from immune cells attenuated liver fibrosis, whereas deletion of IL-22 exacerbated fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protected mice from bile duct ligation-induced liver fibrosis.

Conclusions

IL-17 induces liver fibrosis through multiple mechanisms in mice. Reagents that block these pathways might be developed as therapeutics for patients with cirrhosis.

Section snippets

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.

References (30)

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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.

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