The Role of IFNγ in the Immune Pathogenesis of Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, characterized by proliferation of the bile ducts that is accompanied by inflammatory bowel disease in two thirds of the patients. High levels of Interferon-γ (IFNγ) and IFNγ-induced chemokines have been detected in liver tissue and plasma of PSC patients. Aim of this study is to analyze the role of IFNγ-producing or IFNγ-activated cells in the immune pathogenesis of PSC. Therefore, IFNγ was neutralized in multidrug resistance protein 2 knockout (Mdr2-/-) mice representing a model that resembles PSC.

Mdr2-/- mice (10 weeks old) were treated with anti-IFNγ antibody for 2 weeks. Histological analysis allowed the examination of inflammation and fibrosis. To investigate the cytotoxic potential of non-parenchymal liver cells (NPCs) after restimulation with PMA/Ionomycin, in vitro studies were performed and analyzed by FACS. Real time PCR was applied to examine the gene expression of targets involved in the IFNγ signaling pathway.

The fibrosis level of anti-IFNγ treated mice was reduced compared to the IgG control treated mice. Restimulation of NPCs showed a reduced frequency of IFNγ-producing NK cells and CD8+ T cells. Both cell populations expressed less CD107 indicating reduced cytotoxicity. In addition, the anti-IFNγ treated mice showed reduced hepatic mRNA expression levels of transcription factors like STAT1, SMAD7 and IRF1.

In conclusion, neutralization of IFNγ in Mdr2-/- mice showed a reduction in liver fibrosis and lymphocytes cytotoxicity. This allows the assumption, that IFNγ is involved in the immune pathogenesis of PSC. Further studies will reveal the specific cell populations involved.