Increased monocyte nuclear factor-kappaB activation and tumor necrosis factor production in alcoholic hepatitis

Increased tumor necrosis factor-a activity has been reported in patients with alcoholic hepatitis and is implicated in its pathogenesis. The aim of this study was to investigate potential mechanisms of increased tumor necrosis factor-a activity in alcoholic hepatitis. Monocyte nuclear factor-kB activity was assessed by electrophoretic mobility shift assay, monocyte tumor necrosis factor-a mRNA was semi-quantitatively assessed by reverse transcriptase polymerase chain reaction, and tumor necrosis factor-a in monocyte culture supernatants was measured. There was significantly greater spontaneous nuclear factor-kB activity in the monocytes of 6 patients with alcoholic hepatitis as compared with that in the monocytes of control subjects. There was spontaneous tumor necrosis factor-a mRNA and tumor necrosis factor-a release from the monocytes of patients with alcoholic hepatitis but not from the monocytes of normal subjects. Endotoxin increased nuclear factor-kB activity and induced tumor necrosis factor-a mRNA and tumor necrosis factor-a release from normal subjects' monocytes. Endotoxin further increased nuclear factor-kB activity, tumor necrosis factor-a mRNA, and tumor necrosis factor-a release from the monocytes of patients with alcoholic hepatitis. Supershift assays indicate that the monocyte nuclear factor-kB activation involves the p50 and p65 subunits. Dysregulated tumor necrosis factor-a metabolism in alcoholic hepatitis monocytes is associated with increased nuclear factor-kB activity and tumor necrosis factor-a mRNA expression.