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Gastroenterology. 2012 Sep;143(3):765-776.e3. doi: 10.1053/j.gastro.2012.05.049. Epub 2012 Jun 8.

Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice.

Author information

1
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California; Department of Hepatology, Qilu Hospital, Shandong University, Jinan, China.
2
Department of Hepatology, Qilu Hospital, Shandong University, Jinan, China.
3
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California.
4
Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, California.
5
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California; Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
6
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California; Department of Medicine III, University Hospital Aachen, Aachen, Germany.
7
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California; Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
8
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California; Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
9
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria; Department of Visceral Surgery and Medicine, Inselspital Bern, Switzerland.
10
Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California.
11
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California. Electronic address: tkisseleva@ucsd.edu.

Abstract

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.

PMID:
22687286
PMCID:
PMC3635475
DOI:
10.1053/j.gastro.2012.05.049
[Indexed for MEDLINE]
Free PMC Article

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