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Science 317 (5834): 121-124

Copyright © 2007 by the American Association for the Advancement of Science

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*

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.

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

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Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.
F. Colotta, P. Allavena, A. Sica, C. Garlanda, and A. Mantovani (2009)
Carcinogenesis 30, 1073-1081
   Abstract »    Full Text »    PDF »
Milk fat globule epidermal growth factor-8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms.
M. Jinushi, M. Sato, A. Kanamoto, A. Itoh, S. Nagai, S. Koyasu, G. Dranoff, and H. Tahara (2009)
J. Exp. Med. 206, 1317-1326
   Abstract »    Full Text »    PDF »
Toll-like receptors as targets in chronic liver diseases.
A Mencin, J Kluwe, and R F Schwabe (2009)
Gut 58, 704-720
   Abstract »    Full Text »    PDF »
Molecular insights into {beta}-galactoside {alpha}2,6-sialyltransferase secretion in vivo.
S. Kitazume, R. Oka, K. Ogawa, S. Futakawa, Y. Hagiwara, H. Takikawa, M. Kato, A. Kasahara, E. Miyoshi, N. Taniguchi, et al. (2009)
Glycobiology 19, 479-487
   Abstract »    Full Text »    PDF »
C/EBP{beta} regulates body composition, energy balance-related hormones and tumor growth.
J. Staiger, M. J. Lueben, D. Berrigan, R. Malik, S. N. Perkins, S. D. Hursting, and P. F. Johnson (2009)
Carcinogenesis 30, 832-840
   Abstract »    Full Text »    PDF »
Predominant modifier of extreme liver cancer susceptibility in C57BR/cdJ female mice localized to 6 Mb on chromosome 17.
S. E.-M. Peychal, A. Bilger, H. C. Pitot, and N. R. Drinkwater (2009)
Carcinogenesis 30, 879-885
   Abstract »    Full Text »    PDF »
Sex-Modified Effect of Hepatitis B Virus Infection on Mortality From Primary Liver Cancer.
N. Wang, Y. Zheng, X. Yu, W. Lin, Y. Chen, and Q. Jiang (2009)
Am. J. Epidemiol. 169, 990-995
   Abstract »    Full Text »    PDF »

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