Regulation by intracellular glutathione of TNF-alpha-induced p38 MAP kinase activation and RANTES production by human pulmonary vascular endothelial cells.

Abstract

We have previously shown that p38 mitogen-activated protein (MAP) kinase regulates tumor necrosis factor-alpha (TNF-alpha)-induced RANTES production by human pulmonary vascular endothelial cells, and that sensitivity to TNF-alpha is inversely correlated with cellular reduction and oxidation (redox) state. However, a regulatory role of intracellular glutathione (GSH) in TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production has not been determined. In the present study, therefore, we extended our previous studies and focused on redox regulation on p38 MAP kinase activation. Human pulmonary vascular endothelial cells were exposed to N-acetylcysteine (NAC) or buthionine sulfoximine (BSO), and then TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production were determined. The results showed that 1) NAC attenuated TNF-alpha-induced p38MAP kinase activation and RANTES production 2) SB 203580 as the specific inhibitor of p38 MAP kinase activity attenuated TNF-alpha-induced RANTES production 3) BSO facilitated TNF-alpha-induced p38 MAP kinase activation and RANTES production 4) SB 203580 attenuated BSO-mediated facilitation of TNF-alpha-induced RANTES production. These results indicated that TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human pulmonary vascular endothelial cells are inversely regulated by intracellular GSH levels.