Intracellular glutathione regulates tumour necrosis factor-α-induced p38 MAP kinase activation and RANTES production by human bronchial epithelial cells

Background RANTES plays an important role in the production of allergic inflammation of the airway through its chemotactic activity for eosinophils. The cellular reduction and oxidation (redox) changes are involved in the activation of p38 mitogen-activated protein (MAP) kinase and the induction of cytokine expression. It has previously been shown that tumour necrosis factor (TNF)-MA activates p38 mitogen-activated protein (MAP) kinase to produce cytokine, including RANTES, that N-acetylcysteine (NAC) attenuates cytokine production by human bronchial epithelial cells (BECs), and that sensitivity to TNF alpha is inversely correlated with cellular redox state. However, a role of cellular redox regulated by intracellular glutathione (GSH) in TNF alpha -induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs has not been determined. Objective Human BECs were exposed to NAG or buthionine sulfoximine (BSO). TNF alpha- induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs were then examined in order to clarify these issues. Results The results showed that: NAC attenuated TNF alpha -induced p38 MAP kinase activation and RANTES production; SE 203580 as the specific inhibitor of p38 MAP kinase activity attenuated TNF-alpha -induced RANTES production; BSO facilitated TNF-alpha -induced p38 MAP kinase activation and RANTES production; SE 203580 attenuated BSO-mediated facilitation of TNF-alpha -induced RANTES production; and the intracellular GSH increased in NAG-treated cells, whereas the intracellular GSH was reduced in BSO-treated cells. Conclusions These results indicate that cellular redox regulated by GSH is critical for TNF-alpha -induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs.