title: IL-17A synergistically enhances bile acid-induced inflammation during obstructive cholestasis.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: Kate M
authors.initials: KM
authors.lastname: O'Brien
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
authors.forename: Katryn M
authors.initials: KM
authors.lastname: Allen
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Rockwell
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
authors.forename: Keara
authors.initials: K
authors.lastname: Towery
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan. Electronic address: copple@msu.edu.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Copple
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000008:administration & dosage; D001652:Bile Ducts / Q000187:drug effects / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002452:Cell Count; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D002779:Cholestasis / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D024042:Collagen Type I / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013656:Taurocholic Acid / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000199:Actins; D057134:Antibodies, Neutralizing; D001647:Bile Acids and Salts; D015415:Biomarkers; D054426:Chemokine CXCL2; D024042:Collagen Type I; C404915:Cxcl2 protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger; C544013:alpha-smooth muscle actin, mouse; D013656:Taurocholic Acid