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

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.

• Authors: Fanli Meng, Kai Wang, Tomonori Aoyama, Sergei I Grivennikov, YongHan Paik, David Scholten, Min Cong, Keiko Iwaisako, Xiao Liu, Mingjun Zhang, Christoph H Österreicher, Felix Stickel, Klaus Ley, David A Brenner, Tatiana Kisseleva
• Journal: Gastroenterology (Gastroenterology) Vol. 143 Issue 3 Pg. 765-776.e3 (Sep 2012) ISSN: 1528-0012 [Electronic] United States
• PMID: 22687286 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Collagen Type I
• Il17a protein, mouse
• Il17ra protein, mouse
• Inflammation Mediators
• Interleukin-1
• Interleukin-17
• Interleukin-23
• Interleukin-6
• Interleukins
• Receptors, Interleukin-17
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha
• Carbon Tetrachloride

Topics

• Animals
• Bile Ducts (surgery)
• Bone Marrow Transplantation
• Carbon Tetrachloride
• Cell Line
• Collagen Type I (metabolism)
• Disease Progression
• Gene Expression Regulation
• Genotype
• Hepatic Stellate Cells (immunology, metabolism, pathology)
• Humans
• Inflammation Mediators (administration & dosage, metabolism)
• Interleukin-1 (metabolism)
• Interleukin-17 (administration & dosage, deficiency, genetics, metabolism)
• Interleukin-23 (deficiency, genetics)
• Interleukin-6 (metabolism)
• Interleukins (administration & dosage, deficiency, genetics)
• Kupffer Cells (immunology, metabolism, pathology)
• Ligation
• Liver (immunology, metabolism, pathology)
• Liver Cirrhosis, Alcoholic (immunology, pathology)
• Liver Cirrhosis, Experimental (etiology, genetics, immunology, metabolism, pathology, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phenotype
• Receptors, Interleukin-17 (deficiency, genetics)
• STAT3 Transcription Factor (deficiency, genetics)
• Signal Transduction
• Time Factors
• Transforming Growth Factor beta1 (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Interleukin-22