Silymarin Suppresses TNF-Induced Activation of NF-κB, c-Jun N-Terminal Kinase, and Apoptosis

Abstract

AbstractSilymarin is a polyphenolic flavonoid derived from milk thistle (Silybum marianum) that has anti-inflammatory, cytoprotective, and anticarcinogenic effects. How silymarin produces these effects is not understood, but it may involve suppression of NF-κB, a nuclear transcription factor, which regulates the expression of various genes involved in inflammation, cytoprotection, and carcinogenesis. In this report, we investigated the effect of silymarin on NF-κB activation induced by various inflammatory agents. Silymarin blocked TNF-induced activation of NF-κB in a dose- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of ΙκBα, an inhibitor of NF-κB. Silymarin blocked the translocation of p65 to the nucleus without affecting its ability to bind to the DNA. NF-κB-dependent reporter gene transcription was also suppressed by silymarin. Silymarin also blocked NF-κB activation induced by phorbol ester, LPS, okadaic acid, and ceramide, whereas H2O2-induced NF-κB activation was not significantly affected. The effects of silymarin on NF-κB 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 TNF-induced production of reactive oxygen intermediates and lipid peroxidation. Overall, the inhibition of activation of NF-κB and the kinases may provide in part the molecular basis for the anticarcinogenic and anti-inflammatory effects of silymarin, and its effects on caspases may explain its role in cytoprotection.