Betulinic acid suppresses carcinogen-induced NF-κB activation through inhibition of IκBα kinase and p65 phosphorylation:: Abrogation of cyclooxygenase-2 and matrix metalloprotease-9
Betulinic acid suppresses carcinogen-induced NF-κB activation through inhibition of IκBα kinase and p65 phosphorylation:: Abrogation of cyclooxygenase-2 and matrix metalloprotease-9
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DOI：
10.4049/jimmunol.171.6.3278
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发表时间：
2003-09-15
影响因子：
4.4
通讯作者：
Aggarwal, BB
中科院分区：
文献类型：
--
作者：
Takada, Y;Aggarwal, BB
桦木酸 (BA) 是一种从白桦树皮中分离出来的五环三萜，据报道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 如何介导这些影响尚不清楚。由于转录因子 NF-kappaB 在生长调节、炎症和免疫反应中的关键作用，我们假设 BA 调节该因子的活性。在这项研究中，我们研究了 BA 对由多种炎症和致癌物质激活的 NF-kappaB 和 NF-kappaB 调节的基因表达的影响。 BA 抑制 TNF、PMA、香烟烟雾、冈田酸、IL-1 和 H2O2 诱导的 NF-κB 激活。 NF-κB 激活的抑制不具有细胞类型特异性。 BA 抑制 IkappaBalpha 激酶的激活，从而消除 IkappaBalpha 的磷酸化和降解。我们发现 BA 抑制 TNFR 1、TNFR 相关死亡结构域、TNFR 相关因子 2、NF-kappaB 诱导激酶和 IkappaBα 激酶激活的 NF-kappaB。用这种三萜类化合物处理细胞还抑制了 NF-kappaB 依赖性报告基因表达以及炎症刺激诱导的 NF-kappaB 调节基因产物（例如环氧合酶 2 和基质金属蛋白酶 9）的产生。此外，BA 还能增强 TNF 诱导的细胞凋亡。总的来说，我们的结果表明 BA 抑制由致癌物和炎症刺激诱导的 NF-kappaB 激活和 NF-kappaB 调节的基因表达。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。
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 H2O2. 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.