Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis

Silymarin is a polyphenolic flavonoid derived from milk thistle (Silybum ma rianum) that has anti-inflammatory, cytoprotective, and anticarcinogenic ef fects, How silymarin produces these effects is not understood, but it may i nvolve suppression of NF-kappa B, a nuclear transcription factor, which reg ulates the expression of various genes involved in inflammation, cytoprotec tion, and carcinogenesis. In this report, we investigated the effect of sil ymarin on NF-kappa B activation induced by various inflammatory agents. Sil ymarin blocked TNF-induced activation of NF-kappa B in a dose- and time-dep endent manner. This effect was mediated through inhibition of phosphorylati on and degradation of I kappa B alpha, an inhibitor of NF-kappa B. Silymari n blocked the translocation of p65 to the nucleus without affecting its abi lity to bind to the DNA, NF-kappa B-dependent reporter gene transcription w as also suppressed by silymarin, Silymarin also blocked NF-kappa B activati on induced by phorbol ester, LPS, okadaic acid, and ceramide, whereas H2O2- induced NF-kappa B activation was not significantly affected, The effects of silymarin on NF-kappa B activation were specific, as AP-1 activation was unaffected. Silymarin also inhibited the TNF-induced activation of mitogen -activated protein kinase kinase and c-Jun N-terminal kinase and abrogated TNF-induced cytotoxicity and caspase activation. Silymarin suppressed the T NF-induced production of reactive oxygen intermediates and lipid peroxidati on. Overall, the inhibition of activation of NF-kappa B and the kinases may provide in part the molecular basis for the anticarcinogenic and anti-infl ammatory effects of silymarin, and its effects on caspases may explain its role in cytoprotection.