Takada Yasunari, Aggarwal Bharat B
Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
J Immunol. 2003 Sep 15;171(6):3278-86. doi: 10.4049/jimmunol.171.6.3278.
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-kappaB 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-kappaB and NF-kappaB-regulated gene expression activated by a variety of inflammatory and carcinogenic agents. BA suppressed NF-kappaB activation induced by TNF, PMA, cigarette smoke, okadaic acid, IL-1, and H(2)O(2). The suppression of NF-kappaB activation was not cell-type specific. BA suppressed the activation of IkappaBalpha kinase, thus abrogating the phosphorylation and degradation of IkappaBalpha. We found that BA inhibited NF-kappaB activated by TNFR 1, TNFR-associated death domain, TNFR-associated factor 2, NF-kappaB-inducing kinase, and IkappaBalpha kinase. Treatment of cells with this triterpinoid also suppressed NF-kappaB-dependent reporter gene expression and the production of NF-kappaB-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-kappaB and NF-kappaB-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.
桦木酸（BA）是一种从白桦树皮中分离出的五环三萜，据报道它是肿瘤细胞凋亡的选择性诱导剂。它还具有抗炎和免疫调节特性。BA如何介导这些作用尚不清楚。由于转录因子核因子κB（NF-κB）在生长调节、炎症和免疫反应中起关键作用，我们推测BA可调节该因子的活性。在本研究中，我们调查了BA对由多种炎症和致癌剂激活的NF-κB及NF-κB调控的基因表达的影响。BA抑制了由肿瘤坏死因子（TNF）、佛波酯（PMA）、香烟烟雾、冈田酸、白细胞介素-1（IL-1）和过氧化氢（H₂O₂）诱导的NF-κB激活。NF-κB激活的抑制并非细胞类型特异性的。BA抑制了IκBα激酶的激活，从而消除了IκBα的磷酸化和降解。我们发现BA抑制了由肿瘤坏死因子受体1（TNFR 1）、TNFR相关死亡结构域、TNFR相关因子2、NF-κB诱导激酶和IκBα激酶激活的NF-κB。用这种三萜类化合物处理细胞也抑制了NF-κB依赖的报告基因表达以及由炎症刺激诱导的NF-κB调控的基因产物如环氧合酶-2和基质金属蛋白酶-9的产生。此外，BA增强了TNF诱导的细胞凋亡。总体而言，我们的结果表明BA抑制了由致癌物和炎症刺激诱导的NF-κB激活及NF-κB调控的基因表达。这可能为BA介导细胞凋亡、抑制炎症和调节免疫反应的能力提供分子基础。
