Resveratrol down-regulates interferon-γ-inducible inflammatory genes in macrophages: molecular mechanism via decreased STAT-1 activation

Resveratrol (trans-3,4'.5-trihydroxystilbene) is one of nonflavonoid polyphenolic phytoalexins found in various plant species, a number of which are components of human diet including grapes and red wines. Resveratrol has exerted several beneficial effects with anti-inflammation, cardioprotection and cancer chemoprevention. However, its mechanisms of action are not completely understood. In this study, we investigated effects of resveratrol on inflammatory gene expression in interferon (IFN)-gamma alone-stimulated macrophages and proposed a molecular basis underlying the action. Resveratrol inhibited IFN-gamma-induced production of nitric oxide (NO), IFN-gamma-inducible protein-10 (IP-10), or the monokine induced by IFN-gamma (MIG) in RAW 264.7 macrophages and also that of NO in primary macrophages derived from bone marrows of C3H/HeJ (toll-like receptor-4(-/-)) mice. Moreover, resveratrol diminished IFN-gamma-induced protein levels of inducible NO synthase (iNOS), attenuated mRNA levels of iNOS. IP-10 or MIG as well as inhibited IFN-gamma-induced promoter activity of iNOS gene, indicating that the phytoalexin could down-regulate inflammatory genes at the transcription level. To understand a mechanism of the action, we tested resveratrol could affect the signal transducers and activation of transcription-1 (STAT-1), a pivotal transcription factor in IFN-gamma-induced expression of inflammatory genes. Resveratrol inhibited IFN-gamma-induced transcriptional activity of STAT-1 in macrophages and also IFN-gamma-induced Tyr(701) or Ser(727) phosphorylation of STAT-1. We then focused on protein kinases upstream STAT-1 phosphorylation. Resveratrol inhibited IFN-gamma-induced activation of Janus kinase-2 (JAK-2) and also the extracellular signal-regulated kinase, in which JAK-2 was more sensitive. Taken together, this study proposes a new mechanism of resveratrol, blocking JAK/STAT-1 pathway that controls inflammatory responses in IFN-gamma-activated macrophages. (C) 2011 Elsevier Inc. All rights reserved.