Cytokines and the molecular mechanisms of alcoholic liver disease.
This manuscript was given as a plenary lecture at the annual meeting of the Research Society on Alcoholism in July of 1999. It describes the general mechanisms by which tumor necrosis factor (TNF) alpha, an injury-related cytokine, promotes liver regeneration and then details how TNF-initiated hepatotrophic signals are inhibited by chronic ethanol consumption. There is evidence that chronic ethanol exposure impairs the TNF-dependent activation of stress-activated protein kinases and some of their targets, including the growth-stimulatory DNA binding protein, c-Jun. Ethanol exposure also prevents TNF from activating the redox-sensitive transcription factor, NF kappa B, in regenerating hepatocytes. These effects are followed by decreased hepatocyte proliferation, as well as by impaired induction of TNF-regulated survival factors, such as Bcl-xL, in the liver. Thus, chronic ethanol consumption may damage the liver by inhibiting the hepatotrophic and hepatoprotective actions of TNFalpha and other growth-regulatory cytokines.
Diehl
A M
AM
Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA. amdiehl@welchlink.welch.jhu.edu
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002492:Central Nervous System Depressants / Q000506:poisoning; D016207:Cytokines / Q000502:physiology; D000431:Ethanol / Q000506:poisoning; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000401:mortality / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D002492:Central Nervous System Depressants; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol