Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF-κB through the suppression of p65 phosphorylation
Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF-κB through the suppression of p65 phosphorylation
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DOI：
10.4049/jimmunol.179.10.7121
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发表时间：
2007-11-15
影响因子：
4.4
通讯作者：
Doseff, Andrea I.
中科院分区：
文献类型：
--
作者：
Nicholas, Courtney;Batra, Sanjay;Doseff, Andrea I.
LPS通过激活调节炎性细胞因子产生的信号事件刺激单核/巨噬细胞。芹菜素是一种在水果和蔬菜中大量发现的类黄酮，具有抗增殖和抗炎活性，其机制尚不明确。在这项研究中，我们证明了芹菜素抑制lps刺激的人单核细胞和小鼠巨噬细胞中促炎细胞因子IL-1 β、IL-8和TNF的产生。即使在LPS刺激后给予芹菜素，对促炎细胞因子产生的抑制作用仍然存在。利用NF-kappa B报告基因构建的瞬时转染实验表明，芹菜素在lps刺激的小鼠巨噬细胞中抑制NF-kappa B的转录活性。在芹菜素lps刺激的人单核细胞中观察到经典的蛋白酶体依赖性nf - κ B抑制剂I κ B α的降解。使用EMSA，我们发现芹菜素不会改变nf - κ B-DNA在人单核细胞中的结合活性。相反，我们表明，作为非规范途径的一部分，芹菜素通过p65亚基中Ser536的低磷酸化和LPS刺激下IKK复合物的失活来调节NF-kappa B的活性。在用芹菜素处理的lps刺激的小鼠巨噬细胞中，Ser536磷酸化的降低被IKK β的过度表达所克服。此外，我们的研究表明，芹菜素抑制体内LPS诱导的TNF和致死剂量LPS诱导的死亡。总的来说，这些发现提示了芹菜素抑制炎症和调节体内免疫反应的分子机制。
LPS stimulates monocytes/macrophages through the activation of signaling events that modulate the production of inflammatory cytokines. Apigenin, a flavonoid abundantly found in fruits and vegetables, exhibits anti-proliferative and anti-inflammatory activities through poorly defined mechanisms. In this study, we demonstrate that apigenin inhibits the production of proinflammatory cytokines IL-1 beta, IL-8, and TNF in LPS-stimulated human monocytes and mouse macrophages. The inhibitory effect on proinflammatory cytokine production persists even when apigenin is administered after LPS stimulation. Transient transfection experiments using NF-kappa B reporter constructs indicated that apigenin inhibits the transcriptional activity of NF-kappa B in LPS-stimulated mouse macrophages. The classical proteasome-dependent degradation of the NF-kappa B inhibitor I kappa B alpha was observed in apigenin LPS-stimulated human monocytes. Using EMSA, we found that apigenin does not alter NF-kappa B-DNA binding activity in human monocytes. Instead we show that apigenin, as part of a non-canonical pathway, regulates NF-kappa B activity through hypophosphorylation of Ser536 in the p65 subunit and the inactivation of the IKK complex stimulated by LPS. The decreased phosphorylation on Ser536 observed in LPS-stimulated mouse macrophages treated with apigenin was overcome by the over-expression of IKK beta. In addition, our studies indicate that apigenin inhibits in vivo LPS-induced TNF and the mortality induced by lethal doses of LPS. Collectively, these findings suggest a molecular mechanism by which apigenin suppresses inflammation and modulates the immune response in vivo.