title: Critical role of interleukin-17/interleukin-17 receptor axis in mediating Con A-induced hepatitis.
abstract: Concanavalin A (Con A)-induced hepatitis is thought to be a T-cell-mediated disease with active destruction of liver cells. Interleukin (IL)-17 is a cytokine produced principally by CD4(+) T cells. However, whether IL-17/IL-17 receptor (IL-17/IL-17R)-mediated responses are involved in T-cell-mediated Con A-induced liver injury remains unclear. In this study, we found that IL-17 expression was highly elevated in liver tissues during Con A-induced hepatitis. The increased levels of IL-17 were paralleled with the severity of liver injury reflected by Alanine aminotransaminase and histological assay as well as the secretion of tumor necrosis factor (TNF)-α and IL-6. Blockage of IL-17 significantly ameliorated Con A-induced hepatitis, while overexpression of IL-17 systemically resulted in massive hepatocyte necrosis in mice. Furthermore, overexpression of an IL-17R immunoglobulin G1 fusion protein significantly attenuated liver inflammation after acute Con A treatment. High expression of IL-17R on Kupffer cells was also observed along with the production of cytokines including TNF-α and IL-6. Inhibition of Kupffer cells by gadolinium chloride completely prevented Con A-induced liver injury and cytokine release. Finally, IL-17-expressing CD4(+) T and natural killer T cells were greatly increased in Con A-injected mice compared with that in controls. Overall, our results indicate that IL-17R signaling is critically involved in the pathogenesis in Con A-induced hepatitis, and blockade of IL-17/IL-17R signaling pathway may represent a novel therapeutic intervention in human autoimmune-related hepatitis.
authors.affiliation: Department of Immunology, Shanghai Medical College, Key Laboratory of Molecular Medicine of Ministry of Education, Fudan University, Shanghai, PR China.
authors.forename: Shu
authors.initials: S
authors.lastname: Yan
authors.forename: Luman
authors.initials: L
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D003208:Concanavalin A / Q000494:pharmacology*; D006505:Hepatitis / Q000209:etiology / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007249:Inflammation; D020381:Interleukin-17 / Q000096:biosynthesis*; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D053722:Receptors, Interleukin-17 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007074:Immunoglobulin G; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D003208:Concanavalin A