Gradisar Helena, Keber Mateja Mancek, Pristovsek Primoz, Jerala Roman
National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.
J Leukoc Biol. 2007 Oct;82(4):968-74. doi: 10.1189/jlb.1206727. Epub 2007 Jul 3.
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.
姜黄素是香料姜黄的主要成分，用于饮食和传统医学，尤其在印度次大陆广泛应用。抗炎活性和对脂多糖（LPS）信号传导的抑制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髓样分化蛋白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。加入MD - 2后，姜黄素的荧光发射增强，且吸收峰向蓝光方向移动，表明姜黄素转移到了疏水环境中。姜黄素不与MD - 2的游离巯基形成共价键，C133F突变体仍保留被姜黄素结合和抑制的特性。姜黄素的结合位点与LPS的结合位点重叠。这导致通过TLR4对LPS信号传导的MyD88依赖性和非依赖性信号通路受到抑制，表明MD - 2是姜黄素抑制对细菌感染的先天性免疫反应的重要靶点之一。这一发现，除了姜黄素在饮食中的使用与印度胃癌低发病率之间的相关性外，可能对由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。
