Nonsteroidal anti-inflammatory drug metabolism potentiates interferon alfasignaling by increasing STAT1 phosphorylation

A sustained response to standard interferon therapy for chronic hepatitis C has been demonstrated in no more than 25% of patients. To improve interfer on alfa (IFN-alpha) antiviral effect, a number of combination therapies wit h IFNs plus other drugs have been proposed for both relapser and nonrespond er hepatitis C virus (HCV)-infected patients. Although the causes of IFN re sistance in subsets of HCV-infected patients are unknown, both viral and ho st factors have been involved, including defects in IFN signal transduction and IFN-alpha/beta receptor down-regulation. Here, we report that nonstero idal anti-inflammatory drugs (NSAIDs), which have been proposed for IFN-alp ha combination therapy in nonresponders, potentiate IFN-alpha signaling. We found that, in the hepatoma cell lines, CCL13/Chang and HepG2, indomethaci n, a selective cyclo-oxygenase 1 and 2 (COX-1 and COX-2) inhibitor, increas es IFN-alpha stimulation of interferon-stimulated response element (ISRE)-d ependent transcription in a dose-dependent manner. interestingly, maximal p otentiation was observed with suboptimal IFN-alpha concentrations. Indometh acin exerts its effects by synergizing with IFN-alpha in inducing STAT1 act ivation by phosphorylation, without affecting concurrent Jak1 phosphorylati on, Our data indicate that blockade of arachidonic acid (AA) metabolism by indomethacin activates a signaling pathway that converges on STAT1 activati on to potentiate IFN-alpha-dependent gene activation.