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CORTICOSTEROIDS INHIBIT INTERFERON-ALFA (IFN) SIGNALING VIA THE JAK-STAT PATHWAY BY INCREASING EXPRESSION OF SUPRESSORS OF CYTOKINE SIGNALING(SOCS)

S Khatkar, EL Renner
Section of Hepatology/Department of Medicine, University of Manitoba, Winnipeg, Manitoba

BACKGROUND/AIM: IFN signaling via the Jak-Stat pathway involves Stat1 phosphorylation/translocation into the nucleus, is negatively regulated by SOCS1 and 3, and plays a pivotal role in eliciting an antiviral state in hepatitis C virus (HCV) infected hepatocytes (Blindenbacher, Gastroenterology 2003). HCV-related end-stage liver disease is the single most common indication for liver transplantation (OLT). After OLT, HCV re-infection of the graft is universal, associated with a 10-100-fold increase in HCV-viremia, responds poorly to IFN based therapy and follows an aggressive course leading to graft cirrhosis in ~25% of patients within a few years. Use of (high dose bolus) corticosteroids was repeatedly found to be associated with accelerated progression (Beringuer, J Hepatol 2005). We have recently shown that Dexamethasone (DEX) inhibits IFN-induced Stat1 phopshorylation/signaling into the nucleus (Khatkar & Renner, Hepatology [Abstract], in press). We hypothesized that this is due to DEX increasing SOCS1 and/or 3 expression.
METHODS: C57BL/6 mice (n=4 per group) were treated for 5 days with 10mg/kg i.p. DEX/vehicle daily and injected (tail vein) with 1000U/g b.w. murine IFN/vehicle 20min prior to harvesting the livers. Liver cytosolic extracts were prepared and SOCS1/3 mRNA and protein expression determined by real-time PCR and Western blotting/densitometry, respectively. Results were normalized for GAPDH mRNA and beta-actin expression, respectively, and analyzed by ANOVA followed by Newman-Keuls test.
RESULTS: SOCS1 and 3 mRNA was increased on average 2-3 fold, and SOCS3 (but not SOCS1) protein expression 1.5-fold in DEX/IFN treated (all p<0.05) compared to vehicle/IFN and vehicle/vehicle treated animals which did not significantly differ.
CONCLUSION: This indicates that DEX inhibits IFN induced Stat1 phosphorylation/signaling into the nucleus by increasing SOCS, in particular SOCS3 expression, is consistent with corticosteroids blunting the IFN induced antiviral state and may pertain to the increased HCV-viremia/accelerated course and poor response to IFN based therapy of recurrent hepatitis C after OLT.

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