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B, c-Jun N-Terminal Kinase, and Apoptosis1
Departments of
*
Molecular Oncology and
Bone Marrow Transplantation, Cytokine Research Laboratory, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
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-
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-B activation induced by various inflammatory agents. Silymarin
blocked TNF-induced activation of NF-B in a dose- and time-dependent
manner. This effect was mediated through inhibition of phosphorylation
and degradation of IB
, an inhibitor of NF-B. Silymarin
blocked the translocation of p65 to the nucleus without affecting its
ability to bind to the DNA. NF-B-dependent reporter gene
transcription was also suppressed by silymarin. Silymarin also blocked
NF-B activation induced by phorbol ester, LPS, okadaic acid, and
ceramide, whereas H2O2-induced NF-B
activation was not significantly affected. The effects of silymarin on
NF-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-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.
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