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INFLAMMATION AND IMMUNOPHARMACOLOGY

Inhibition of Inducible Nitric-Oxide Synthase Expression by (5R)-5-Hydroxytriptolide in Interferon-- and Bacterial Lipopolysaccharide-Stimulated Macrophages

Laboratories of Immunopharmacology and Chemistry, Graduate School of the Chinese Academy of Sciences, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, People's Republic of China (R.Z., W.T., P.-L.H., X.-Y.L., Y.-F.Y., Y.-C.L., J.-P.Z.); and Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China (S.-X.Z., J.-G.G.)

(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)-, lipopolysaccharide (LPS), and IFN- plus LPS. It also reduced the production of tumor necrosis factor- 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- 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--stimulated Raw 264.7 cells, LLDT-8 suppressed the gene transcription of signal transducer and activator of transcription 1 and interferon regulatory factor (IRF)-1, but it displayed no apparent effect on IFN- 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 IB; and ameliorated the DNA binding activity of nuclear factor-B (NF-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--triggered IRF-1 expression and LPS-triggered MAPK phosphorylation and NF-B activation.

Address correspondence to: Dr. Jian-Ping Zuo, Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China. E-mail: jpzuo{at}mail.shcnc.ac.cn

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				R. Zhou, W. Tang, Y.-X. Ren, P.-L. He, F. Zhang, L.-P. Shi, Y.-F. Fu, Y.-C. Li, S. Ono, H. Fujiwara, et al. (5R)-5-Hydroxytriptolide Attenuated Collagen-Induced Arthritis in DBA/1 Mice via Suppressing Interferon-{gamma} Production and Its Related Signaling J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 35 - 44. [Abstract] [Full Text] [PDF]