EFFECTS OF ACETALDEHYDE AND TNFα ON THE INHIBITORY KAPPA B- α PROTEIN AND NUCLEAR FACTOR KAPPA B ACTIVATION IN HEPATIC STELLATE CELLS

Aims: Increased plasma tumour necrosis α (TNFα) and elevated monocyte nuclear factor kappa B (NF-κB) 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 TNFα inhibits, transcription of the type I collagen promoters and type I collagen production. NF-κB, an inhibitor of the type I collagen promoters, is increased by both acetaldehyde and TNFα. This study determined the effects of acetaldehyde in comparison to the effects of TNFα on inhibitory kappa B-α (IκB-α) protein and NF-κB activation in hepatic stellate cells. Methods: Activated rat hepatic stellate cells in culture were exposed to acetaldehyde or TNFα for short periods of time, following which the cells were harvested for the determination of IκB-α protein, IκB-α kinase activity and nuclear NF-κB. Results: Acetaldehyde increased IκB-α kinase activity and decreased IκB-α after 10 min of exposure, with recovery towards control levels at 20 min. In contrast, TNFα resulted in higher IκB-α kinase activity at 20 min than at 10 min, and similar low IκB-α at 10 and 20 min. Both acetaldehyde and TNFα enhanced nuclear NF-κB (p65), but acetaldehyde alone also increased NF-κB (p50). Conclusions: TNFα and acetaldehyde independently activate NF-κB by rapid enhancement of IκB-α kinase activity and degradation of IkB-α protein. Increased TNFα is the principal mechanism for the elevation of NF-κB in severe alcoholic hepatitis. The elevation of NF-κB due to TNFα enhance liver injury, but inhibit fibrogenesis. In contrast, the effect of acetaldehyde in activating NF-κB 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-κB. ( Received 27 July 2004; first review notified 16 September 2004; in revised form 18 October 2004; accepted 19 October 2004 )