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The Journal of Immunology, 2004, 173: 4207-4217.
Copyright © 2004 by The American Association of Immunologists

Andrographolide Attenuates Inflammation by Inhibition of NF-{kappa}B Activation through Covalent Modification of Reduced Cysteine 62 of p501

Yi-Feng Xia2,*, Bu-Qing Ye2,*, Yi-Dan Li2,*, Jian-Guo Wang§, Xiang-Jiu He{dagger}, Xianfeng Lin{ddagger}, Xinsheng Yao{dagger}, Dawei Ma{ddagger}, Arne Slungaard§, Robert P. Hebbel§, Nigel S. Key§ and Jian-Guo Geng3,*,§

* Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; {dagger} Department of Phytochemistry, Shenyang Pharmaceutical University, Shenyang, Liaoning, China; {ddagger} State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; and § Vascular Biology Center and Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN 55455

NF-{kappa}B is a central transcriptional factor and a pleiotropic regulator of many genes involved in immunological responses. During the screening of a plant extract library of traditional Chinese herbal medicines, we found that NF-{kappa}B activity was potently inhibited by andrographolide (Andro), an abundant component of the plant Andrographis that has been commonly used as a folk remedy for alleviation of inflammatory disorders in Asia for millennia. Mechanistically, it formed a covalent adduct with reduced cysteine (62) of p50, thus blocking the binding of NF-{kappa}B oligonucleotide to nuclear proteins. Andro suppressed the activation of NF-{kappa}B in stimulated endothelial cells, which reduced the expression of cell adhesion molecule E-selectin and prevented E-selectin-mediated leukocyte adhesion under flow. It also abrogated the cytokine- and endotoxin-induced peritoneal deposition of neutrophils, attenuated septic shock, and prevented allergic lung inflammation in vivo. Notably, it had no suppressive effect on I{kappa}B{alpha} degradation, p50 and p65 nuclear translocation, or cell growth rates. Our results thus reveal a unique pharmacological mechanism of Andro’s protective anti-inflammatory actions.




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