alpha-Viniferin suppresses the signal transducer and activation of transcription-1 (STAT-1)-inducible inflammatory genes in interferon-gamma-stimulated macrophages.
alpha-Viniferin, an oligostilbene of trimeric resveratrol, has been reported to have anti-inflammatory potential in carrageenin-induced paw edema or adjuvant-induced arthritis in animal models. However, little is known about the molecular basis. In this study, alpha-viniferin at 3 - 10 microM dose-dependently inhibited interferon (IFN)-gamma-induced Ser(727) phosphorylation of the signal transducer and activation of transcription-1 (STAT-1), a pivotal transcription factor controlling IFN-gamma-targeted genes, in RAW 264.7 macrophages, and also IFN-gamma-induced activation of the extracellular signal-regulated kinase (ERK)-1, a protein kinase upstream of the Ser(727) phosphorylation of STAT-1. However, alpha-viniferin, only at a higher concentration of 10 microM, inhibited Janus kinase 2-mediated Tyr(701) phosphorylation of STAT-1 in the cells. To understand STAT-1-dependent inflammatory responses, we quantified nitric oxide (NO) or chemokines. alpha-Viniferin at 3 - 10 muM dose-dependently inhibited IFN-gamma-induced production of NO, IFN-gamma-inducible protein-10 (IP-10), or the monokine induced by IFN-gamma (MIG) in RAW 264.7 cells and also that of NO in primary macrophages-derived from C57BL/6 mice. Furthermore, alpha-viniferin diminished IFN-gamma-induced protein levels of inducible NO synthase (iNOS), attenuated mRNA levels of iNOS, IP-10, or MIG as well as inhibited promoter activity of the iNOS gene. In conclusion, this study proposes an anti-inflammatory mechanism of alpha-viniferin, down-regulating STAT-1-inducible inflammatory genes via inhibiting ERK-mediated STAT-1 activation in IFN-gamma-stimulated macrophages.
Chung
Eun Yong
EY
College of Pharmacy, Chungbuk National University, Korea.
Roh
Eunmiri
E
Kwak
Jeong-Ah
JA
Lee
Heun-Sik
HS
Lee
Seung Ho
SH
Lee
Chong-Kil
CK
Han
Sang-Bae
SB
Kim
Youngsoo
Y
D000818:Animals; D001483:Base Sequence; D001572:Benzofurans / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D017931:DNA Primers; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000502:physiology*
D001572:Benzofurans; D018925:Chemokines; D017931:DNA Primers; D050794:STAT1 Transcription Factor; D009569:Nitric Oxide; C064176:alpha-viniferin; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D011494:Protein Kinases