Dual effects of heat stress on tumor necrosis factor-|[alpha]|-induced hepatocyte apoptosis in mice

摘要

The major heat shock protein, HSP70, plays a critical role in cell survival in response to stress, possibly by inhibiting a number of antisurvival pathways. However, heat stress (HS) and HSPs also sensitize cells to certain apoptotic stimuli, such as TNF-. To clarify the relations between HS and apoptosis, we examined the differential effects of the intensity of HS on liver injury and apoptosis induced by TNF- in mice. TNF- was injected into D-galactosamine (GalN)-sensitized mice that were pretreated with or without HS. Liver injury was assessed biochemically and histologically. In GalN-sensitized mice, application of HS for 7 days led to significant enhancement of TNF--induced hepatotoxicity, despite upregulation of HSP70 in the liver. In contrast, application of HS for 1 day led to attenuation of TNF--induced liver injury. Repeated HS decreased the levels of the FLICE inhibitory protein short (FLIPS) and activated caspase-8 in the liver. The caspase-8 inhibitor Z-IETD-FMK effectively protected both the nontreated and HS-pretreated mice from the hepatotoxicity induced by GalN/TNF-. HS shows dual effects on TNF--induced hepatocyte apoptosis. Exposure to repeated HS, but not to single HS, leads to enhancement of TNF--induced hepatocyte apoptosis via the interaction of FLIP and caspase-8.