Gender Disparity in Liver Cancer Due to Sex Differences in MyD88-Dependent IL-6 Production

TLDR

Hepatocellular carcinoma predominantly affects men, a pattern also observed in mice exposed to the chemical carcinogen diethylnitrosamine. The study aims to show that estrogen suppresses IL‑6 production by Kupffer cells, thereby lowering liver cancer risk in females and offering a potential prevention strategy for males. Male mice exhibit higher IL‑6 levels and greater hepatocarcinogenesis after DEN, which is eliminated by IL‑6 or MyD88 deletion, while estrogen suppresses Kupffer‑cell IL‑6 production and lowers circulating IL‑6, linking sex hormones to gender disparities in liver cancer.

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.