MD-2 as the target of curcumin in the inhibition of response to LPS
MD-2 as the target of curcumin in the inhibition of response to LPS
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DOI：
10.1189/jlb.1206727
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发表时间：
2007-10-01
影响因子：
5.5
通讯作者：
Jerala, Roman
中科院分区：
文献类型：
--
作者：
Gradisar, Helena;Keber, Mateja Mancek;Jerala, Roman
姜黄素是香料姜黄的主要成分，用于饮食和传统医学，特别是在印度次大陆。抗炎活性和抑制 LPS 信号传导是其众多活性中的一部分。我们发现姜黄素以亚微摩尔亲和力与骨髓分化蛋白 2 (MD-2) 结合，MD-2 是内毒素表面受体复合物 MD-2/TLR4 的 LPS 结合成分。添加 MD-2 后，姜黄素的荧光发射增加，吸光度最大向蓝色移动，表明姜黄素转移到疏水环境中。姜黄素不与MD-2的游离硫醇基团形成共价键，并且C133F突变体保留了姜黄素的结合和抑制作用。姜黄素的结合位点与 LPS 的结合位点重叠。这导致通过 TLR4 抑制 MyD88 依赖和不依赖的 LPS 信号传导途径，表明 MD-2 是姜黄素抑制细菌感染先天免疫反应的重要靶标之一。这一发现，除了印度饮食中姜黄素的使用与胃癌低发病率之间的相关性外，可能对细菌感染引起的慢性炎症性疾病的治疗和流行病学具有重要意义。
Curcumin is the main constituent of the spice turmeric, used in diet and in traditional medicine, particularly across the Indian subcontinent. Anti-inflammatory activity and inhibition of LPS signaling are some of its many activities. We show that curcumin binds at submicromolar affinity to the myeloid differentiation protein 2 (MD-2), which is the LPS-binding component of the endotoxin surface receptor complex MD-2/TLR4. Fluorescence emission of curcumin increases with an absorbance maximum shift toward the blue upon the addition of MD-2, indicating the transfer of curcumin into the hydrophobic environment. Curcumin does not form a covalent bond to the free thiol group of MD-2, and C133F mutant retains the binding and inhibition by curcumin. The binding site for curcumin overlaps with the binding site for LPS. This results in the inhibition of MyD88-dependent and -independent signaling pathways of LPS signaling through TLR4, indicating that MD-2 is one of the important targets of curcumin in its suppression of the innate immune response to bacterial infection. This finding, in addition to the correlation between the dietary use of curcumin and low incidence of gastric cancer in India, may have important implications for treatment and epidemiology of chronic inflammatory diseases caused by bacterial infection.