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National Institute of Environmental Health Sciences

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Publication Detail

Title: IL-17A synergistically enhances bile acid-induced inflammation during obstructive cholestasis.

Authors: O'Brien, Kate M; Allen, Katryn M; Rockwell, Cheryl E; Towery, Keara; Luyendyk, James P; Copple, Bryan L

Published In Am J Pathol, (2013 Nov)

Abstract: During obstructive cholestasis, increased concentrations of bile acids activate ERK1/2 in hepatocytes, which up-regulates early growth response factor 1, a key regulator of proinflammatory cytokines, such as macrophage inflammatory protein 2 (MIP-2), which, in turn, exacerbates cholestatic liver injury. Recent studies have indicated that IL-17A contributes to hepatic inflammation during obstructive cholestasis, suggesting that bile acids and IL-17A may interact to regulate hepatic inflammatory responses. We treated mice with an IL-17A neutralizing antibody or control IgG and subjected them to bile duct ligation. Neutralization of IL-17A prevented up-regulation of proinflammatory cytokines, hepatic neutrophil accumulation, and liver injury, indicating an important role for IL-17A in neutrophilic inflammation during cholestasis. Treatment of primary mouse hepatocytes with taurocholic acid (TCA) increased the expression of MIP-2. Co-treatment with IL-17A synergistically enhanced up-regulation of MIP-2 by TCA. In contrast to MIP-2, IL-17A did not affect up-regulation of Egr-1 by TCA, indicating that IL-17A does not affect bile acid-induced activation of signaling pathways upstream of early growth response factor 1. In addition, bile acids increased expression of IL-23, a key regulator of IL-17A production in hepatocytes in vitro and in vivo. Collectively, these data identify bile acids as novel triggers of the IL-23/IL-17A axis and suggest that IL-17A promotes hepatic inflammation during cholestasis by synergistically enhancing bile acid-induced production of proinflammatory cytokines by hepatocytes.

PubMed ID: 24012680 Exiting the NIEHS site

MeSH Terms: Actins/metabolism; Animals; Antibodies, Neutralizing/pharmacology; Bile Acids and Salts/administration & dosage; Bile Ducts/drug effects; Bile Ducts/pathology; Biomarkers/metabolism; Cell Count; Chemokine CXCL2/genetics; Chemokine CXCL2/metabolism; Cholestasis/complications; Cholestasis/metabolism*; Cholestasis/pathology*; Collagen Type I/metabolism; Hepatocytes/drug effects; Hepatocytes/metabolism; Hepatocytes/pathology; Inflammation/complications; Inflammation/metabolism*; Inflammation/pathology*; Interleukin-17/metabolism*; Interleukin-23/genetics; Interleukin-23/metabolism; Ligation; Liver/drug effects; Liver/injuries; Liver/pathology; Macrophages/drug effects; Macrophages/pathology; Male; Mice; Mice, Inbred C57BL; Neutralization Tests; Neutrophils/drug effects; Neutrophils/metabolism; Neutrophils/pathology; RNA, Messenger/genetics; RNA, Messenger/metabolism; Signal Transduction; Taurocholic Acid/pharmacology; Up-Regulation/drug effects

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