title: Resveratrol down-regulates interferon-γ-inducible inflammatory genes in macrophages: molecular mechanism via decreased STAT-1 activation.
abstract: 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)-γ alone-stimulated macrophages and proposed a molecular basis underlying the action. Resveratrol inhibited IFN-γ-induced production of nitric oxide (NO), IFN-γ-inducible protein-10 (IP-10), or the monokine induced by IFN-γ (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-γ-induced protein levels of inducible NO synthase (iNOS), attenuated mRNA levels of iNOS, IP-10 or MIG as well as inhibited IFN-γ-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-γ-induced expression of inflammatory genes. Resveratrol inhibited IFN-γ-induced transcriptional activity of STAT-1 in macrophages and also IFN-γ-induced Tyr(701) or Ser(727) phosphorylation of STAT-1. We then focused on protein kinases upstream STAT-1 phosphorylation. Resveratrol inhibited IFN-γ-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-γ-activated macrophages.
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea.
authors.forename: Eun Yong
authors.initials: EY
authors.lastname: Chung
authors.forename: Byung Hak
authors.initials: BH
authors.lastname: Kim
authors.forename: Jin-Tae
authors.initials: JT
authors.lastname: Hong
authors.forename: Chong-Kil
authors.initials: CK
authors.lastname: Lee
authors.forename: Byeongwoo
authors.initials: B
authors.lastname: Ahn
authors.forename: Sang-Yoon
authors.initials: SY
authors.lastname: Nam
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D000077185:Resveratrol; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: D054357:Chemokine CXCL10; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D013267:Stilbenes; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D053614:Janus Kinase 2; D000077185:Resveratrol