S-adenosylmethionine attenuates the lipopolysaccharide-induced expression of the gene for tumour necrosis factor alpha

Intracellular deficiency of S-adenosylmethionine (AdoMet) and elevated seru m concentrations of tumour necrosis factor alpha (TNF) are hallmarks of tox in-induced liver injury. In these models, the administration of either exog enous AdoMet or antibody/soluble receptor for TNF attenuates the injury, We have demonstrated previously that the administration of exogenous AdoMet t o AdoMet-deficient rats attenuated lipopolysaccharide (LPS)induced liver in jury and serum TNF concentrations. Here we report that AdoMet lowered the a mount of TNF secreted by LPS-stimulated murine macrophage cells (RAW 264.7) in a dose-dependent manner. The inhibition of TNF release was correlated w ith changes in the steady-state TNF mRNA concentrations. Changes in TNF mRN A were not due to its altered stability and might have been due to an atten uation of the transcription rate of the TNF gene. The inhibition of TNF rel ease in RAW cells was not mediated by GSH because treatment with AdoMet did not increase intracellular GSH. In addition, N-acetylcysteine, whereas it did increase GSH concentration, had no effect on LPS-stimulated TNF release in these cells. Exogenous AdoMet also attenuated LPS-induced serum TNF lev els in normal rats sensitized with lead. Thus AdoMet administration might e xert its hepatoprotective effects at least in part by its inhibitory effect on expression of the gene for TNF.