Transgenic overexpression of interleukin-8 in mouse liver protects against galactosamine/endotoxin toxicity.

BACKGROUND/AIMS: CXC chemokines function as survival factors for several types of cells. In this study, we investigated whether CXC chemokines promote survival of liver cells following an apoptotic stimulus in vivo. METHODS: Apoptosis was induced in mouse liver by treatment with galactosamine and endotoxin (Gal/ET). The influence of CXC chemokines was investigated by comparing Gal/ET responses in wild-type (WT) mice to those in mice with a transgene encoding the CXC chemokine interleukin-8 (IL-8 TG). RESULTS: IL-8 TG mice displayed less apoptosis and better survival after Gal/ET treatment than did WT mice (60% fewer TUNEL-positive cells at 6 h; 36% better survival at 24 h). Gal/ET toxicity was also preventable in WT mice by pre-treatment with IL-8. Notably, IL-8 was not protective against hepatic apoptosis due to anti-Fas or concanavalin A. In Gal/ET-treated mice, IL-8 promoted liver cell survival by interfering with the mitochondrial pathway of apoptosis. Survival was not attributable to activation of NF-kappaB or up-regulation of anti-apoptotic proteins, but coincided instead with activation of Akt and phosphorylation of the pro-apoptotic protein Bad. CONCLUSIONS: IL-8 protects liver cells from Gal/ET-mediated apoptosis by signaling through phosphatidylinositol-3 kinase (PI-3K). This is in keeping with the reported mechanism of chemokine-related survival in other tissues.