Nonsteroidal anti-inflammatory drug metabolism potentiates interferon alfa signaling by increasing STAT1 phosphorylation
1999; Lippincott Williams & Wilkins; Volume: 30; Issue: 2 Linguagem: Inglês
10.1002/hep.510300224
ISSN1527-3350
AutoresStefania Giambartolomei, Marco Artini, C. Almerighi, Sabrina Maria Moavero, Massimo Levrero, Clara Balsano,
Tópico(s)Pharmacological Effects of Natural Compounds
ResumoA sustained response to standard interferon therapy for chronic hepatitis C has been demonstrated in no more than 25% of patients. To improve interferon alfa (IFN-α) antiviral effect, a number of combination therapies with IFNs plus other drugs have been proposed for both relapser and nonresponder hepatitis C virus (HCV)-infected patients. Although the causes of IFN resistance in subsets of HCV-infected patients are unknown, both viral and host factors have been involved, including defects in IFN signal transduction and IFN-α/β receptor down-regulation. Here, we report that nonsteroidal anti-inflammatory drugs (NSAIDs), which have been proposed for IFN-α combination therapy in nonresponders, potentiate IFN-α signaling. We found that, in the hepatoma cell lines, CCL13/Chang and HepG2, indomethacin, a selective cyclo-oxygenase 1 and 2 (COX-1 and COX-2) inhibitor, increases IFN-α stimulation of interferon-stimulated response element (ISRE)-dependent transcription in a dose-dependent manner. Interestingly, maximal potentiation was observed with suboptimal IFN-α concentrations. Indomethacin exerts its effects by synergizing with IFN-α in inducing STAT1 activation by phosphorylation, without affecting concurrent Jak1 phosphorylation. Our data indicate that blockade of arachidonic acid (AA) metabolism by indomethacin activates a signaling pathway that converges on STAT1 activation to potentiate IFN-α-dependent gene activation.
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