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Infection and Immunity, November 2002, p. 6294-6301, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.6294-6301.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Tumor Necrosis Factor Alpha-Induced Interleukin-8 Production via NF-{kappa}B and Phosphatidylinositol 3-Kinase/Akt Pathways Inhibits Cell Apoptosis in Human Hepatocytes

Yosuke Osawa,1 Masahito Nagaki,1* Yoshiko Banno,2 David A. Brenner,3 Takahiko Asano,1 Yoshinori Nozawa,4 Hisataka Moriwaki,1 and Shigeru Nakashima2

First Department of Internal Medicine,1 Department of Biochemistry, Gifu University School of Medicine, Gifu 500-8705,2 Gifu International Institute of Biotechnology, Mitake, Gifu 505-0116, Japan,4 Departments of Medicine, Biochemistry, and Biophysics, The University of North Carolina, Chapel Hill, North Carolina 275993

Received 15 March 2002/ Returned for modification 3 May 2002/ Accepted 2 August 2002

Tumor necrosis factor alpha (TNF-{alpha}) not only induces apoptotic signals but also causes antiapoptotic and regenerative responses in the liver. However, the molecular mechanism(s) of the latter events remains unclear. In the present study, we examined TNF-{alpha}-induced genes in Hc human normal (unsensitized) hepatocytes by cDNA microarray analysis. Interleukin-8 (IL-8) induction was the most pronounced of the upregulated genes. The IL-8 protein level was also increased. IL-8 belongs to the ELR-CXC chemokine family and appears to exert mitogenic and antiapoptotic functions in other cell systems. IL-8 expression by TNF-{alpha} was inhibited when two survival signals, nuclear factor {kappa}B (NF-{kappa}B) and phosphatidylinositol 3-kinase (PI3K)/Akt, were inhibited by a mutant form of inhibitor of NF-{kappa}B (I{kappa}B); by dominant negative (kinase-dead) Akt; or by treatment with LY 294002, an inhibitor of PI3K. TNF-{alpha} induced apoptosis in Hc cells that were sensitized by inhibition of NF-{kappa}B and PI3K activation. IL-8 administration protected mice against concanavalin A-induced hepatitis in vivo. IL-8 also rescued the sensitized Hc cells, at least in part, from TNF-{alpha}-induced apoptosis in vitro. TNF-{alpha} inhibited DNA synthesis in unsensitized Hc cells in the absence of serum. Exogenous IL-8 reversed, though anti-IL-8 neutralization antibody enhanced, growth inhibition by TNF-{alpha}. These results indicate that IL-8, the production of which is stimulated by TNF-{alpha}, inhibits apoptosis of sensitized hepatocytes and releases normal (unsensitized) hepatocytes from growth inhibition induced by TNF-{alpha}.

* Corresponding author. Mailing address: First Department of Internal Medicine, Gifu University School of Medicine, Tsukasamachi-40, Gifu 500-8705, Japan. Phone: 81-58-267-2843. Fax: 81-58-262-8484. E-mail: mnagaki{at}cc.gifu-u.ac.jp.

Editor: S. H. E. Kaufmann

Infection and Immunity, November 2002, p. 6294-6301, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.6294-6301.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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