Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production
Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production
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DOI：
10.1126/science.1140485
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发表时间：
2007-07-06
期刊：
影响因子：
56.9
通讯作者：
Karin, Michael
中科院分区：
文献类型：
--
作者：
Naugler, Willscott E.;Sakurai, Toshiharu;Karin, Michael
肝细胞癌是最常见的肝癌，主要发生在男性。在服用化学致癌物二乙基亚硝胺(DEN)的小鼠身上也发现了类似的性别差异。DEN给药导致男性血清白介素6(IL-6)浓度的升高幅度大于女性。此外，消融IL-6消除了小鼠肝癌发生的性别差异。DEN暴露以一种依赖于Toll样受体适配器蛋白MyD88的方式促进Kupffer细胞(KCs)产生IL-6，该蛋白的消融也保护雄性小鼠免受DEN诱导的肝癌的发生。在DEN处理的雄性小鼠中，雌激素抑制KCs与坏死性肝细胞接触时分泌IL-6，并降低循环中IL-6的浓度。我们认为，雌激素介导的抑制KCs产生IL-6降低了女性患肝癌的风险，这些发现可能用于预防男性的肝癌。
Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men. Similar gender disparity is seen in mice given a chemical carcinogen, diethylnitrosamine ( DEN). DEN administration caused greater increases in serum interleukin-6 (IL-6) concentration in males than it did in females. Furthermore, ablation of IL-6 abolished the gender differences in hepatocarcinogenesis in mice. DEN exposure promoted production of IL-6 in Kupffer cells (KCs) in a manner dependent on the Toll-like receptor adaptor protein MyD88, ablation of which also protected male mice from DEN-induced hepatocarcinogenesis. Estrogen inhibited secretion of IL-6 from KCs exposed to necrotic hepatocytes and reduced circulating concentrations of IL-6 in DEN-treated male mice. We propose that estrogen-mediated inhibition of IL-6 production by KCs reduces liver cancer risk in females, and these findings may be used to prevent HCC in males.