title: Intracellular glutathione regulates tumour necrosis factor-alpha-induced p38 MAP kinase activation and RANTES production by human bronchial epithelial cells.
abstract: 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 TNFalpha is inversely correlated with cellular redox state. However, a role of cellular redox regulated by intracellular glutathione (GSH) in TNFalpha-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 NAC or buthionine sulfoximine (BSO). TNFalpha-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 TNFalpha-induced p38 MAP kinase activation and RANTES production; SB 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; SB 203580 attenuated BSO-mediated facilitation of TNF-alpha-induced RANTES production; and the intracellular GSH increased in NAC-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.
authors.affiliation: First Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Gon
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: I
authors.initials: I
authors.lastname: Takeshita
authors.forename: T
authors.initials: T
authors.lastname: MacHino
authors.forename: T
authors.initials: T
authors.lastname: Horie
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002461:Cell Line, Transformed; D018946:Chemokine CCL5 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D005978:Glutathione / Q000494:pharmacology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018946:Chemokine CCL5; D014409:Tumor Necrosis Factor-alpha; D019328:Buthionine Sulfoximine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; D000111:Acetylcysteine