Gender Disparity in Liver Cancer Due to Sex Differences in MyD88-Dependent IL-6 Production
Willscott E. Naugler,1,2
Toshiharu Sakurai,1
Sunhwa Kim,1
Shin Maeda,3
KyoungHyun Kim,1
Ahmed M. Elsharkawy,1,4
Michael Karin1*
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.
1 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, University of California, San Diego, CA 93093, USA.
2 Department of Medicine, Division of Gastroenterology, University of California, San Diego, CA 93093, USA.
3 Division of Gastroenterology, The Institute for Adult Diseases, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005, Japan.
4 Liver Research Group, University of Newcastle, Newcastle Upon Tyne NE2 4HH, UK.
* To whom correspondence should be addressed: 9500 Gilman Road, Mail Code 0723 University of California, San Diego, San Diego, CA 92093–0636, USA. E-mail: karinoffice{at}ucsd.edu
