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B Activation Through Inhibition of IB
Kinase and p65 Phosphorylation: Abrogation of Cyclooxygenase-2 and Matrix Metalloprotease-9
Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
Betulinic acid (BA), a pentacyclic triterpene isolated from the bark of the white birch tree, has been reported to be a selective inducer of apoptosis in tumor cells. It also exhibits anti-inflammatory and immunomodulatory properties. How BA mediates these effects is not known. Because of the critical role of the transcription factor NF-
B in growth modulatory, inflammatory, and immune responses, we postulated that BA modulates the activity of this factor. In this study we investigated the effect of BA on NF-B and NF-B-regulated gene expression activated by a variety of inflammatory and carcinogenic agents. BA suppressed NF-B activation induced by TNF, PMA, cigarette smoke, okadaic acid, IL-1, and H2O2. The suppression of NF-B activation was not cell-type specific. BA suppressed the activation of IB
kinase, thus abrogating the phosphorylation and degradation of IB. We found that BA inhibited NF-B activated by TNFR 1, TNFR-associated death domain, TNFR-associated factor 2, NF-B-inducing kinase, and IB kinase. Treatment of cells with this triterpinoid also suppressed NF-B-dependent reporter gene expression and the production of NF-B-regulated gene products such as cyclooxygenase-2 and matrix metaloproteinase-9 induced by inflammatory stimuli. Furthermore, BA enhanced TNF-induced apoptosis. Overall, our results indicated that BA inhibits activation of NF-B and NF-B-regulated gene expression induced by carcinogens and inflammatory stimuli. This may provide a molecular basis for the ability of BA to mediate apoptosis, suppress inflammation, and modulate the immune response.
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