Inhibition of inducible nitric-oxide synthase expression by (5R)-5-hydroxytriptolide in interferon-gamma- and bacterial lipopolysaccharide-stimulated macrophages

	Inhibition of inducible nitric-oxide synthase expression by (5R)-5-hydroxytriptolide in interferon-gamma- and bacterial lipopolysaccharide-stimulated macrophages
	Zhou, R; Zheng, SX; Tang, W; He, PL; Li, XY; Yang, YF; Li, YC; Geng, JG; Zuo, JP
刊名	JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
	2006
卷号	316 期号:1 页码:121-128
通讯作者	Zuo, JP (reprint author), Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol, Grad Sch,State Key Lab Drug Res, 555 Zuchongzhi Rd Hi Tech Pk, Shanghai 201203, Peoples R China.,jpzuo@mail.shcnc.ac.cn
英文摘要	(5R)-5-Hydroxytriptolide (LLDT-8) is a novel analog of triptolide that has antiarthritic, hepatoprotective, and antiallogenic transplantation-rejective effects. In the present study, we report that LLDT-8 inhibited nitric oxide (NO) production and inducible nitric-oxide synthase (iNOS) expression in macrophages. LLDT-8 significantly attenuated NO production, in a dose-dependent manner, in primary peritoneal macrophages and a macrophage cell line of Raw 264.7 cells following stimulation with interferon (IFN)-gamma, lipopolysaccharide (LPS), and IFN-gamma plus LPS. It also reduced the production of tumor necrosis factor-alpha from LPS-stimulated Raw 264.7 cells. To further elucidate the mechanism responsible for the inhibition of NO, we examined the effect of LLDT-8 on IFN-gamma and LPS-induced iNOS expression. Indeed, LLDT-8 prevented NO generation by inhibiting iNOS expression at mRNA level and protein level, rather than by interfering its enzymatic activity. In IFN-gamma-stimulated Raw 264.7 cells, LLDT-8 suppressed the gene transcription of signal transducer and activator of transcription 1 alpha and interferon regulatory factor (IRF)-1, but it displayed no apparent effect on IFN-gamma receptor level on cell surface. After LPS challenge, LLDT-8 further abrogated the expression of LPS receptor complex, including CD14, Toll-like receptor 4, and myeloid differentiation protein-2; decreased the LPS-induced phosphorylation of stress-activated protein kinase/c-Jun NH2-terminal kinase, extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase ( MAPK); retarded the degradation of I kappa B alpha; and ameliorated the DNA binding activity of nuclear factor-kappa B (NF-kappa B) to nuclear proteins that accounts for transcriptional regulation of iNOS. Taken together, these results suggest that LLDT-8 reduces NO production and iNOS expression by inhibiting IFN-gamma-triggered IRF-1 expression and LPS-triggered MAPK phosphorylation and NF-kappa B activation.
学科主题	Pharmacology & Pharmacy
类目[WOS]	Pharmacology & Pharmacy
关键词[WOS]	WILFORDII HOOK-F ; ACTIVATED PROTEIN-KINASE ; NF-KAPPA-B ; TRANSCRIPTION ; ARTHRITIS ; GENE ; TRIPTOLIDE ; INDUCTION ; PATHWAYS ; MICE
收录类别	SCI
语种	英语
WOS记录号	WOS:000234140400015
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/1656]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Zhou, R,Zheng, SX,Tang, W,et al. Inhibition of inducible nitric-oxide synthase expression by (5R)-5-hydroxytriptolide in interferon-gamma- and bacterial lipopolysaccharide-stimulated macrophages[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,2006,316(1):121-128.
APA	Zhou, R.,Zheng, SX.,Tang, W.,He, PL.,Li, XY.,...&Zuo, JP.(2006).Inhibition of inducible nitric-oxide synthase expression by (5R)-5-hydroxytriptolide in interferon-gamma- and bacterial lipopolysaccharide-stimulated macrophages.JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,316(1),121-128.
MLA	Zhou, R,et al."Inhibition of inducible nitric-oxide synthase expression by (5R)-5-hydroxytriptolide in interferon-gamma- and bacterial lipopolysaccharide-stimulated macrophages".JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 316.1(2006):121-128.