Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production

Willscott E. Naugler, Toshiharu Sakurai, Sunhwa Kim, Shin Maeda, Kyoung Hyun Kim, Ahmed M. Elsharkawy, Michael Karin

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1254 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)121-124
Number of pages4
JournalScience
Volume317
Issue number5834
DOIs
StatePublished - Jul 6 2007

ASJC Scopus subject areas

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    Naugler, W. E., Sakurai, T., Kim, S., Maeda, S., Kim, K. H., Elsharkawy, A. M., & Karin, M. (2007). Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science, 317(5834), 121-124. https://doi.org/10.1126/science.1140485