Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.
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.
Naugler
Willscott E
WE
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, University of California, San Diego, CA 93093, USA.
Sakurai
Toshiharu
T
Kim
Sunhwa
S
Maeda
Shin
S
Kim
Kyounghyun
K
Elsharkawy
Ahmed M
AM
Karin
Michael
M
D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage; D004052:Diethylnitrosamine / Q000008:administration & dosage / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D009336:Necrosis; D010052:Ovariectomy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics
D015850:Interleukin-6; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D004052:Diethylnitrosamine; D004958:Estradiol; D002251:Carbon Tetrachloride