title: Interleukin-27 and IFNγ regulate the expression of CXCL9, CXCL10, and CXCL11 in hepatitis.
abstract: Interleukin-27 (IL-27) belongs to the IL-6/IL-12 family of cytokines, associated with different inflammatory diseases and orchestrates its biological activity via common heterodimeric receptor composed of WSX-1 (IL-27Rα) and gp130. The present study was aimed to investigate the regulation of CXCL9, CXCL10, and CXCL11 chemokines in hepatic cells (human LX-2 cell line derived from normal human stellate cells (HSC), primary human hepatocytes, HSC, and HepG2 cells) and concanavalin A (ConA)-induced liver inflammation. We demonstrated that IL-27, but not IL-6, induced/up-regulated CXCR3 ligand genes (CXCL9, CXCL10, and CXCL11; out of 26 selected genes) in a STAT1-dependent manner in hepatic cells in vitro both at transcript and protein levels. In ConA-induced T cell-mediated hepatic model, we showed that soluble IL-27/IFNγ was elevated following ConA hepatitis in association with increased CXCL9, CXCL10, and CXCL11 expression in the liver. The exogenous IL-27 administration induced CXCR3 ligands in mouse liver at 4 h with any significant effect on recruitment of CXCR3(+) immune cells in the liver. The neutralization of IL-27 during ConA hepatitis differentially modulated (transcript vs protein expression) CXCR3 ligands and IFNγ during ConA-induced hepatitis with down-regulated expression of CXCL9 and CXCL10 at transcript level. The IFNγ, complementary regulated the expression of CXCR3 ligands as their up-regulation during ConA hepatitis, was abolished in IFNγ KO mice. In summary, IL-27 up-regulated the CXCL9, CXCL10, and CXCL11 chemokine expression in hepatic cells. IL-27 regulated CXCR3 ligand expression in IFNγ-dependent manner during acute hepatitis suggesting a complementary role of IL-27 and IFNγ to moderate liver inflammation via regulation of CXCR3 ligands.
  
  
  CONCLUSIONS
  IL-27 up-regulated CXCR3 ligand expression in human hepatic cells in vitro. IL-27 up-regulated CXCR3 ligand expression and secretion in ConA hepatitis in vivo. CXCR3 ligand expression was down-regulated by blocking IL-27 or IFNγ deficiency. IL-27 modulated liver injury by regulation of CXCR3 ligands in IFNγ-dependent manner.
authors.affiliation: CHU Angers, ex-Inserm U564, 4 rue Larrey, 49933, Angers Cedex 09, France.
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Basset
authors.affiliation: CHU Angers, ex-Inserm U564, 4 rue Larrey, 49933, Angers Cedex 09, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevalier
authors.affiliation: CHU Angers, ex-Inserm U564, 4 rue Larrey, 49933, Angers Cedex 09, France.|Etablissement Français du Sang, Rue Pierre Jean Gineste, 35016, Rennes, France.
authors.forename: Yannic
authors.initials: Y
authors.lastname: Danger
authors.affiliation: U.1085 Inserm, IRSET, Institut de Recherche en Santé-Environnement-Travail, Université de Rennes 1, Biosit, 2 Avenue du Pr., Léon Bernard CS 34317, 35043, Rennes Cedex, France.|Institute of Microbiology, University of Agriculture, Faisalabad, Pakistan.
authors.forename: Muhammad Imran
authors.initials: MI
authors.lastname: Arshad
authors.affiliation: U.1085 Inserm, IRSET, Institut de Recherche en Santé-Environnement-Travail, Université de Rennes 1, Biosit, 2 Avenue du Pr., Léon Bernard CS 34317, 35043, Rennes Cedex, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Piquet-Pellorce
authors.affiliation: CHU Angers, ex-Inserm U564, 4 rue Larrey, 49933, Angers Cedex 09, France.|UMR 6290 CNRS, IGDR, Université de Rennes 1, Biosit, 2 avenue du Professeur Léon Bernard, CS 34317, 35043, Rennes cedex, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Gascan
authors.affiliation: U.1085 Inserm, IRSET, Institut de Recherche en Santé-Environnement-Travail, Université de Rennes 1, Biosit, 2 Avenue du Pr., Léon Bernard CS 34317, 35043, Rennes Cedex, France. michel.samson@univ-rennes1.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Samson
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000235:genetics*; D054371:Chemokine CXCL11 / Q000235:genetics*; D054370:Chemokine CXCL9 / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006505:Hepatitis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006520:Hepatitis, Animal; D006801:Humans; D007371:Interferon-gamma / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D064094:Interleukin-27 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D064094:Interleukin-27; D015850:Interleukin-6; D008024:Ligands; D054367:Receptors, CXCR3; D050791:STAT Transcription Factors; D007371:Interferon-gamma
keywords: CXCR3 ligands; Hepatic cells; IFNγ; IL-27; Liver inflammation