Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice.
OBJECTIVE
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.
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California; Department of Hepatology, Qilu Hospital, Shandong University, Jinan, China.
Fanli
F
Meng
Department of Hepatology, Qilu Hospital, Shandong University, Jinan, China.
Kai
K
Wang
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California.
Tomonori
T
Aoyama
Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, California.
Sergei I
SI
Grivennikov
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.
YongHan
Y
Paik
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California; Department of Medicine III, University Hospital Aachen, Aachen, Germany.
David
D
Scholten
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California.
Min
M
Cong
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.
Keiko
K
Iwaisako
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California.
Xiao
X
Liu
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California.
Mingjun
M
Zhang
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.
Christoph H
CH
Österreicher
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria; Department of Visceral Surgery and Medicine, Inselspital Bern, Switzerland.
Felix
F
Stickel
Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California.
Klaus
K
Ley
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California.
David A
DA
Brenner
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California. Electronic address: tkisseleva@ucsd.edu.
Tatiana
T
Kisseleva
D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D016026:Bone Marrow Transplantation; D002251:Carbon Tetrachloride; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D018450:Disease Progression; D005786:Gene Expression Regulation; D005838:Genotype; D055166:Hepatic Stellate Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D020381:Interleukin-17 / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000172:deficiency / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics; D007728:Kupffer Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008026:Ligation; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000276:immunology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097043:Interleukin-22
D002251:Carbon Tetrachloride; D024042:Collagen Type I; D018836:Inflammation Mediators; D007375:Interleukin-1; D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D007378:Interleukins; D053722:Receptors, Interleukin-17; D050796:STAT3 Transcription Factor; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; C098680:Il17a protein, mouse; C491673:Il17ra protein, mouse; C494087:Stat3 protein, mouse; C508961:Tgfb1 protein, mouse