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

Background RANTES plays an important role in the production of allergic inf lammation of the airway through its chemotactic activity for eosinophils. T he cellular reduction and oxidation (redox) changes are involved in the act ivation of p38 mitogen-activated protein (MAP) kinase and the induction of cytokine expression. It has previously been shown that tumour necrosis fact or (TNF)-MA activates p38 mitogen-activated protein (MAP) kinase to produce cytokine, including RANTES, that N-acetylcysteine (NAC) attenuates cytokin e production by human bronchial epithelial cells (BECs), and that sensitivi ty to TNF alpha is inversely correlated with cellular redox state. However, a role of cellular redox regulated by intracellular glutathione (GSH) in T NF alpha -induced p38 MAP kinase activation and p38 MAP kinase-mediated RAN TES production by human BECs has not been determined. Objective Human BECs were exposed to NAG or buthionine sulfoximine (BSO). T NF alpha- induced p38 MAP kinase activation and p38 MAP kinase-mediated RAN TES production by human BECs were then examined in order to clarify these i ssues. Results The results showed that: NAC attenuated TNF alpha -induced p38 MAP kinase activation and RANTES production; SE 203580 as the specific inhibito r of p38 MAP kinase activity attenuated TNF-alpha -induced RANTES productio n; BSO facilitated TNF-alpha -induced p38 MAP kinase activation and RANTES production; SE 203580 attenuated BSO-mediated facilitation of TNF-alpha -in duced 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 kinas e-mediated RANTES production by human BECs.