Andrographolide attenuates inflammation by inhibition of NF-kappa B activation through covalent modification of reduced cysteine 62 of p50.
NF-kappaB 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-kappaB 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-kappaB oligonucleotide to nuclear proteins. Andro suppressed the activation of NF-kappaB 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 IkappaBalpha 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.
Xia
Yi-Feng
YF
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.
Ye
Bu-Qing
BQ
Li
Yi-Dan
YD
Wang
Jian-Guo
JG
He
Xiang-Jiu
XJ
Lin
Xianfeng
X
Yao
Xinsheng
X
Ma
Dawei
D
Slungaard
Arne
A
Hebbel
Robert P
RP
Key
Nigel S
NS
Geng
Jian-Guo
JG
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000302:isolation & purification / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism*; D004224:Diterpenes / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D019040:E-Selectin / Q000096:biosynthesis / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D006967:Hypersensitivity / Q000473:pathology / Q000517:prevention & control; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D041681:NIH 3T3 Cells; D020556:Neutrophil Infiltration / Q000187:drug effects; D015345:Oligonucleotide Probes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D010538:Peritonitis / Q000473:pathology / Q000517:prevention & control; D011485:Protein Binding / Q000187:drug effects; D012772:Shock, Septic / Q000517:prevention & control; D051996:Transcription Factor RelA
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; D004365:Drugs, Chinese Herbal; D019040:E-Selectin; D006131:Growth Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D015345:Oligonucleotide Probes; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; C030419:andrographolide; D003545:Cysteine