Alcohol and Alcoholism Advance Access originally published online on November 18, 2004
Alcohol and Alcoholism 2005 40(2):96-101; doi:10.1093/alcalc/agh116
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Alcohol & Alcoholism Vol. 40, No. 2 © Medical Council on Alcohol 2005; all rights reserved
EFFECTS OF ACETALDEHYDE AND TNF
ON THE INHIBITORY KAPPA B- PROTEIN AND NUCLEAR FACTOR KAPPA B ACTIVATION IN HEPATIC STELLATE CELLS
1 Department of Medicine and 2 Department of Oncology and Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2195, USA
* Author to whom correspondence should be addressed at: Department of Medicine, 921 Ross Research Building, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205-2195, USA. Tel.: +1 410 955 7856; Fax: +1 410 955 9677; E-mail: emezey{at}jhmi.edu
(Received 27 July 2004; first review notified 16 September 2004; in revised form 18 October 2004; accepted 19 October 2004)
Aims: Increased plasma tumour necrosis 
(TNF) and elevated monocyte nuclear factor kappa B (NF-
B) are associated with liver injury and inflammation in models of alcoholic liver disease and are found to be elevated in monocytes of patients with alcoholic hepatitis. Acetaldehyde enhances, whereas TNF inhibits, transcription of the type I collagen promoters and type I collagen production. NF-B, an inhibitor of the type I collagen promoters, is increased by both acetaldehyde and TNF. This study determined the effects of acetaldehyde in comparison to the effects of TNF on inhibitory kappa B- (IB-) protein and NF-B activation in hepatic stellate cells. Methods: Activated rat hepatic stellate cells in culture were exposed to acetaldehyde or TNF for short periods of time, following which the cells were harvested for the determination of IB- protein, IB- kinase activity and nuclear NF-B. Results: Acetaldehyde increased IB- kinase activity and decreased IB- after 10 min of exposure, with recovery towards control levels at 20 min. In contrast, TNF resulted in higher IB- kinase activity at 20 min than at 10 min, and similar low IB- at 10 and 20 min. Both acetaldehyde and TNF enhanced nuclear NF-B (p65), but acetaldehyde alone also increased NF-B (p50). Conclusions: TNF and acetaldehyde independently activate NF-B by rapid enhancement of IB- kinase activity and degradation of IkB- protein. Increased TNF is the principal mechanism for the elevation of NF-B in severe alcoholic hepatitis. The elevation of NF-B due to TNF enhance liver injury, but inhibit fibrogenesis. In contrast, the effect of acetaldehyde in activating NF-B is associated with increases in both liver injury and fibrogenesis, indicating that the effects of acetaldehyde on fibrogenesis are mediated by cytokines and by trans-acting factors other than NF-B.
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