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 marianum) that has anti-inflammatory, cytoprotective, and anticarcinogenic effects. How silymarin produces these effects is not understood, but it may involve suppression of NF-kappa B, 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-kappa B activation induced by various inflammatory agents. Silymarin blocked TNF-induced activation of NF-kappa B in a dose- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of Iota kappa B alpha, an inhibitor of NF-kappa B. Silymarin blocked the translocation of p65 to the nucleus without affecting its ability to bind to the DNA. NF-kappa B-dependent reporter gene transcription was also suppressed by silymarin. Silymarin also blocked NF-kappa B activation 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 TNF-induced production of reactive oxygen intermediates and lipid peroxidation. Overall, the inhibition of activation of NF-kappa B 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.
Manna
S K
SK
Department of Molecular Oncology, Cytokine Research Laboratory, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Mukhopadhyay
A
A
Van
N T
NT
Aggarwal
B B
BB
D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites / Q000187:drug effects; D002518:Ceramides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004794:Enzyme Repression / Q000187:drug effects / Q000235:genetics; D017930:Genes, Reporter / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D019319:Okadaic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species / Q000378:metabolism; D012838:Silymarin / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D020298:U937 Cells
D002518:Ceramides; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D017382:Reactive Oxygen Species; D012838:Silymarin; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D019319:Okadaic Acid; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; D013755:Tetradecanoylphorbol Acetate