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Interleukin-27 and IFNγ regulate the expression of CXCL9, CXCL10, and CXCL11 in hepatitis

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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.

Key message

  • 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.

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Acknowledgments

This work was supported by Inserm, CNRS, the Ministère de l’Education Nationale de la Recherche et de la Technologie, the University of Rennes 1, and Angers. We thank Julien Daligault, Laurence Preisser, Patrice Chiron, Valentine Genet, and Mariette Lisbonne for their helpful technical assistance. L.B. was supported by a grant from Ministère de la Recherche et de l’Enseignement Supérieur. This study was supported by the CIMATH Program from Région Pays de la Loire and the Ligue Nationale contre le cancer (Comité du Grand Ouest).

Conflict of interest

The authors declare that they have no competing interests.

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Author notes

  1. Yannic Danger

    Present address: Etablissement Français du Sang, Rue Pierre Jean Gineste, 35016, Rennes, France

  2. Muhammad Imran Arshad

    Present address: Institute of Microbiology, University of Agriculture, Faisalabad, Pakistan

Authors and Affiliations

  1. CHU Angers, ex-Inserm U564, 4 rue Larrey, 49933, Angers Cedex 09, France

    Laëtitia Basset, Sylvie Chevalier, Yannic Danger & Hugues Gascan

  2. 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

    Muhammad Imran Arshad, Claire Piquet-Pellorce & Michel Samson

  3. UMR 6290 CNRS, IGDR, Université de Rennes 1, Biosit, 2 avenue du Professeur Léon Bernard, CS 34317, 35043, Rennes cedex, France

    Hugues Gascan

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  1. Laëtitia Basset
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Correspondence to Michel Samson.

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Hugues Gascan and Michel Samson contributed equally to this work.

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Supplemental 1

Figure S1: Screening of IL-27 and IL-6 induced genes in HepG2 cell line. HepG2 cell line serum-starved overnight was activated, or not, by IL-6 and IL-27 (50 ng/ml) during 6 hours as specified. RNAs were extracted and analysed by RT-qPCR, 437 genes were studied (points represented in graph). The relative quantity of genes was normalized with GAPDH housekeeping gene and results were represented in normalized quantity from IL-27 (a) or IL-6 (b) activated cells according to normalized quantity from control (non-activated cells). Only up- or down-regulated genes above or below twice the median were considered as regulated genes. Gene annotated specifically up regulated by IL-27 (bold font style, A), IL-6 (bold font style, B) and gene up regulated by IL-6 and IL-27 (italic font style, A and B). Figure S2: Expression of CXCR3 in liver NKT and NK cells of C57Bl/6 WT mice. The NKT cells were characterized as CD3+ and NK1.1+ cells and NK cells as NK1.1+ and CD3- cells, labelled cells in presence of anti-CXCR3 is plotted (line) together with the control cells incubated with isotype (filled). In parallel, TH cells among CD3+NK1.1- were depicted and show no CXCR3 expression in the liver of untreated C57Bl6 mice. Figure S3: Blocking of murine IL-27 and expression of IL-10, IL-17A and IL-22 cytokines in liver of mice during T-cell mediated hepatitis in vivo. Mice (n=5 per group) received normal goat IgG control or neutralizing antibody against mouse IL-27p28 via tail vein at dose of 200μg in 100μl PBS. Fifteen minutes later, mice were injected via the tail vein with 3mg/Kg of ConA in 100μl PBS for 4h. Control mice received PBS alone. Liver mRNA expression of IL-10, IL-17A and IL-22 cytokines following 4h ConA, Ig control or anti-IL-27 antibody treatment in mice. Results are expressed in normalized quantity with β2M housekeeping gene. Figure S4: Measurement of mRNA expression of CXCL1 chemokine by RT‐qPCR in WT and IFNγ ‐/‐ mice (n=5 in each group) treated with ConA (12 mg/g i.v.) for 6 and 10h, PBS injected mice served as control. Results were expressed in normalized quantity with 18S housekeeping gene. Table S1: Analysis of IL‐27 or IL‐6 induced genes in HepG2, LX2 cell line, primary human hepatocytes and HSC HepG2, LX2 cell line, primary human hepatocytes and HSC were activated with 50ng/ml of IL‐6 or IL‐27 for 6 hours, then RNAs were extracted and analysed by RT‐qPCR. Only the screened 26 genes up‐regulated by IL‐27 and/or IL‐6 in HepG2 cell line were analysed. Results were represented in fold of induction: ratio of normalized quantity IL‐27 or IL‐6 treatment/ normalized relative quantity control. Each reported value represents the increase (or decrease) level in gene expression (relative to the level for naïve controls). Normalized values of <2> expression level that are not regulated relative to levels of non activated controls. (PDF 241 kb)

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Basset, L., Chevalier, S., Danger, Y. et al. Interleukin-27 and IFNγ regulate the expression of CXCL9, CXCL10, and CXCL11 in hepatitis. J Mol Med 93, 1355–1367 (2015). https://doi.org/10.1007/s00109-015-1319-6

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