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Immunology |
B, Activator Protein-1, and c-Jun NH2-Terminal Kinase1
Cytokine Research Laboratory, Department of Bioimmunotherapy [S. K. M., N. K. S., B. B. A.], and Pharmaceutical Development Center [R. A. N., A. C.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
Agents that can suppress the activation of nuclear factor-
B (NF-B)
and activator protein-1 (AP-1) may be able to block tumorigenesis and
inflammation. Oleandrin, a polyphenolic cardiac glycoside derived from
the leaves of Nerium oleander, is a candidate NF-B
and AP-1 modulator. We investigated the effect of oleandrin on NF-B
activation induced by inflammatory agents. Oleandrin blocked tumor
necrosis factor (TNF)-induced activation of NF-B in a concentration-
and time-dependent manner. This effect was mediated through inhibition
of phosphorylation and degradation of IB
, an inhibitor of
NF-B. A proprietary hot water extract of oleander (Anvirzel) also
blocked TNF-induced NF-B activation; subsequent fractionation of the
extract revealed that this activity was attributable to oleandrin. The
effects of oleandrin were not cell type specific, because it blocked
TNF-induced NF-B activation in a variety of cells. NF-B-dependent
reporter gene transcription activated by TNF was also suppressed by
oleandrin. The TNF-induced NF-B activation cascade involving TNF
receptor 1/TNF receptor-associated death domain/TNF receptor-associated
factor 2/NF-B-inducing kinase/IB kinase was interrupted at the
TNF receptor-associated factor 2 and NF-B-inducing kinase sites by
oleandrin, thus suppressing NF-B reporter gene expression. Oleandrin
blocked NF-B activation induced by phorbol ester and
lipopolysaccharide. Oleandrin also blocked AP-1 activation induced by
TNF and other agents and inhibited the TNF-induced activation of c-Jun
NH2-terminal kinase. Overall, our results indicate that
oleandrin inhibits activation of NF-B and AP-1 and their associated
kinases. This may provide a molecular basis for the ability of
oleandrin to suppress inflammation and perhaps tumorigenesis.
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