Cytokine regulation of liver injury and repair

By comparing the hepatic responses to tumor necrosis factor (TNF)-alpha tha t occur during situations that promote liver injury (such. as obesity or ch ronic exposure to ethanol) with those that occur after stimuli (such as par tial hepatectomy) that lead to liver regeneration, it is apparent that hepa tocytes are usually able to constrain noxious responses to TNF-alpha, such as the release of reactive oxygen from mitochondria. It appears that: by pr omptly upregulating survival genes that regulate mitochondrial membrane per meability, hepatocytes are usually able to constrain noxious responses. inc luding the release of mitochondrial-generated reactive oxygen species, that follow exposure to potentially toxic cytokines, such as TNF-alpha. Indeed, transient TNF-alpha-mediated increases in ROS may even be exploited by hep atocytes to evolve a subsequent proliferative response. Thus, the healthy l iver has well-developed defense mechanisms that permit hepatocytes to adapt to cytokine-initiated stress, protecting them from cytokine-mediated letha lity. Nevertheless, these same cytokines may cause liver injury when hepato cytes have been pre-exposed to toxins (e.g. ethanol) that interfere with th eir usual protective responses. Furthermore, while transient adaptations to cytokine-initiated stress permit hepatocytes to survive and proliferate, p ersistence of these anti-apoptotic, adaptative responses las occurs, for ex ample, in fatty livers) may inadvertently enhance hepatocyte vulnerability to necrosis when the liver is confronted by secondary insults that promote mitochondrial membrane depolarization.