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. 2013:2013:389807.
doi: 10.1155/2013/389807. Epub 2013 May 7.

Interferon- γ triggers hepatic stellate cell-mediated immune regulation through MEK/ERK signaling pathway

Xiaodong Gu  1 , Yan Wang, Jianbin Xiang, Zongyou Chen, Lianfu Wang, Lina Lu, Shiguang Qian
Affiliations

Interferon- γ triggers hepatic stellate cell-mediated immune regulation through MEK/ERK signaling pathway

Xiaodong Gu et al. Clin Dev Immunol. 2013.

Abstract

Hepatic stellate cells (HSCs) interact with immune cells to actively participate in regulating immune response in the liver which is mediated by the effector molecules, including B7-H1. We demonstrated here that expression of B7-H1 on HSCs was markedly enhanced by interferon-(IFN-) γ stimulation. IFN- γ stimulated HSCs inhibited T-cell proliferation via induction of T-cell apoptosis (22.1% ± 1.6%). This immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, or inhibitor of the MEK/ERK pathway inhibited IFN- γ mediated expression of B7-H1. Thus, regulation of B7-H1 expression on HSCs by IFN- γ represents an important mechanism that regulates immune responses in the liver favoring tolerogenicity rather than immunogenicity. Involvement of MEK/ERK pathway provides a novel target for therapeutic approaches.

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Figures

Figure 1
Figure 1
Expression of B7-H1 on HSCs in response to INF-γ stimulation. (a) HSCs isolated from B6 mice were exposed to graded concentrations of IFN-γ (0.1–200 U/mL) for 24 hours in vitro and stained with anti-B7-H1 mAb and analyzed by flow cytometry. (b) HSCs were treated with IFN-γ (10 U/mL) for varying times (0.5–24 hours) and analyzed by RT-PCR. (c) HSCs were incubated with IFN-γ (100 U/mL) for the indicated times, and the expression patterns were analyzed by flow cytometry. (d) HSCs isolated from wild type (WT) or IFN-γR1 KO mice or Stat1 KO mice (all on B6 background) were exposed to IFN-γ (100 U/mL) for 48 hours. Cells were stained using anti-B7-H1 mAb and analyzed by flow cytometry. The data are representative of two separate experiments.
Figure 2
Figure 2
MEK/ERK-dependent B7-H1 expression in HSCs. (a) B7-H1 mRNA levels in HSCs measured by RT-PCR after exposure to IFN-γ (10 U/mL) for 6 hours with or without 10 μg/mL CHX or 10 μg/mL ActD for 90 minutes. (b) Flow cytometric analysis of B7-H1 expression in control HSCs (without IFN-γ stimulation) and after 24 hours incubation with IFN-γ with or without 1 hour pretreatment with signal transduction inhibitors, that is, 100 μM U0126 (MEK1/2), 100 μM SP600125 (JNK), and 100 μM LY294002 (PI3 K). (c) Western blot analysis of ERK1/2 phosphorylation in HSCs after incubation with IFN-γ (10 U/mL) or 1 ng/mL PMA, with or without 1 hour preincubation with 100 μM U0126. (d) RT-PCR analysis of B7-H1 mRNA levels in HSCs exposed for 24 hours to IFN-γ (10 U/mL) or 1 ng/mL PMA with or without 1 hour pre-incubation with 100 μM U0126.
Figure 3
Figure 3
T-cell inhibition by HSCs. (a) B6, BALB/c, IFN-γR1 KO, or B7-H1 KO HSCs cultured in uncoated plastics for 7 days were γ-irradiated (50 Gy) and added at the beginning of an MLR culture in which splenic T cells (2 × 105) from BALB/c mice, and irradiated (20 Gy) B6 DCs were cultured at a final T-cell/DC/HSC ratio of 20 : 2 : 1 for 3 days. In some groups, irradiated HSCs pre-incubated with 100 μM U0126 or anti-B7-H1. Controls were without HSCs. The data are representative of three separate experiments. (b) Cells following cultures for 2 or 3 days were double stained with FITC-anti-CD3 and PE-anti-Annexin V for flow analysis. The data demonstrated Annexin V expression in CD3+ populations. In some groups, irradiated HSCs pre-incubated with 100 μM U0126 or anti-B7-H1. Controls were without HSCs. The data are representative of three separate experiments.
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References

    1. Calne RY, Sells RA, Pena JR, et al. Induction of immunological tolerance by porcine liver allografts. Nature. 1969;223(5205):472–476. - PubMed
    1. Qian S, Demetris AJ, Murase N, Rao AS, Fung JJ, Starzl TE. Murine liver allograft transplantation: tolerance and donor cell chimerism. Hepatology. 1994;19(4):916–924. - PMC - PubMed
    1. Farges O, Morris PJ, Dallman MJ. Spontaneous acceptance of liver allografts in the rat: analysis of the immune response. Transplantation. 1994;57(2):171–177. - PubMed
    1. Ilan Y, Sauter B, Chowdhury NR, et al. Oral tolerization to adenoviral proteins permits repeated adenovirus- mediated gene therapy in rats with pre-existing immunity to adenoviruses. Hepatology. 1998;27(5):1368–1376. - PubMed
    1. Yu S, Nakafusa Y, Flye MW, et al. Portal vein administration of donor cells promotes peripheral allospecific hyporesponsiveness and graft tolerance. Surgery. 1994;116(2):229–235. - PubMed

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