Ginsenoside Rh1 suppresses inducible nitric oxide synthase gene expression in IFN-gamma-stimulated microglia via modulation of JAK/STAT and ERK signaling pathways.
Microglial activation plays an important role in the pathogenesis of various neurodegenerative diseases by producing neurotoxic factors, such as pro-inflammatory cytokines and nitric oxide (NO). In the present study, we found that protopanaxatriol ginsenoside Rh1 suppresses NO, ROS, and TNF-alpha production in IFN-gamma-stimulated BV2 microglial cells. Rh1 inhibited the mRNA and protein expression of iNOS and TNF-alpha. To determine the regulatory mechanism of iNOS gene expression by Rh1, promoter analysis was performed. Rh1 significantly suppressed IFN-gamma-induced iNOS promoter activity by inhibiting DNA binding of several transcription factors, such as NF-kappaB, IRF-1, and STAT1. Furthermore, Rh1 inhibited the phosphorylation of JAK1, STAT1, STAT3, and ERK, which are upstream signaling molecules for IFN-gamma-induced iNOS gene expression. The present study demonstrates that Rh1 inhibits IFN-gamma-induced JAK/STAT and ERK signaling pathways and downstream transcription factors, and thereby iNOS gene expression. Therefore, the inhibition of microglial activation by ginsenoside Rh1 may provide potential therapeutic strategy for various neuroinflammatory diseases.
Jung
Ji-Sun
JS
Department of Molecular Medicine, Brain Disease Research Institute, Ewha Womans University School of Medicine, Seoul, Republic of Korea.
Kim
Dong-Hyun
DH
Kim
Hee-Sun
HS
D000818:Animals; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D036145:Ginsenosides / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction
D036145:Ginsenosides; D050791:STAT Transcription Factors; C425564:ginsenoside Rh1; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D053612:Janus Kinases; D048049:Extracellular Signal-Regulated MAP Kinases