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Clinical & Experimental Allergy

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

Authors


S. Hashimoto, First Department of Internal Medicine, Nihon University School of Medicine, 30–1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173–8610, Japan.

Abstract

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 TNFα is inversely correlated with cellular redox state. However, a role of cellular redox regulated by intracellular glutathione (GSH) in TNFα-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs has not been determined.

Human BECs were exposed to NAC or buthionine sulfoximine (BSO). TNFα-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs were then examined in order to clarify these issues.

The results showed that: NAC attenuated TNFα-induced p38 MAP kinase activation and RANTES production; SB 203580 as the specific inhibitor of p38 MAP kinase activity attenuated TNF-α-induced RANTES production; BSO facilitated TNF-α-induced p38 MAP kinase activation and RANTES production; SB 203580 attenuated BSO-mediated facilitation of TNF-α-induced RANTES production; and the intracellular GSH increased in NAC-treated cells, whereas the intracellular GSH was reduced in BSO-treated cells.

These results indicate that cellular redox regulated by GSH is critical for TNF-α-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs.

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