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

Background: We have previously shown that p38 mitogen-activated protein (MA P) kinase regulates tumor necrosis factor-alpha (TNF-alpha)-induced RANTES production by human pulmonary vascular endothelial cells, and that sensitiv ity to TNF-alpha is inversely correlated with cellular reduction and oxidat ion (redox) state. However, a regulatory role of intracellular glutathione (GSH) in TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-med iated RANTES production has not been determined. In the present study, ther efore, we extended our previous studies and focused on redox regulation on p38 MAP kinase activation. Methods: Human pulmonary vascular endothelial cells were exposed to N-acety lcysteine (NAC) or buthionine sulfoximine (BSO), and then TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production we re determined. Results: The results showed that 1) NAC attenuated TNF-alpha-induced p38MAP kinase activation and RANTES pro duction 2) SE 203580 as the specific inhibitor of p38 MAP kinase activity attenuate d TNF-alpha-induced RANTES production 3) BSO facilitated TNF-alpha-induced p38 MAP kinase activation and RANTES p roduction 4) SE 203580 attenuated BSO-mediated facilitation of TNF-alpha-induced RANT ES production. Conclusions: 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 le vels.