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