title: Redox regulation of p38 MAPK activation and expression of ICAM-1 and heme oxygenase-1 in human alveolar epithelial (A549) cells.
abstract: We have explored the potential role of redox events in p38 mitogen-activated protein kinase (MAPK) activation and their relevance to the inducible expression of intercellular adhesion molecule-1 (ICAM-1) and heme oxygenase-1 (HO-1) in A549 cells. Tumor necrosis factor-alpha (TNFalpha) and hydrogen peroxide (H2O2) both activated p38, but only TNFalpha activated nuclear factor-kappaB (NF-kappaB). N-Acetyl-L-cysteine (20 mM) inhibited both H2O2- and TNFalpha-induced p38 phosphorylation (14 +/- 7 and 37 +/- 4% of control, respectively). The mitochondrial complex I and III inhibitors, rotenone and antimycin A, and allopurinol partially inhibited H2O2- but not TNFalpha-induced p38 activation. However, rotenone and antimycin A augmented intracellular oxidative stress measured by dichlorofluorescein fluorescence. TNFalpha, but not H2O2, induced ICAM-1 in A549 cells, which was attenuated by a proteasome inhibitor, but not by the p38 MAPK inhibitor SB203580. In contrast, hemin and hemoglobin, but neither TNFalpha nor H2O2, caused efficient HO-1 expression. However, hemin had no effect on p38 activation and SB203580 did not influence hemin-induced HO-1 protein expression. Collectively, these data suggest that p38 is a cytokine- and oxidative stress-responsive pathway in A549 cells. Whereas NF-kappaB appears crucial in ICAM-1 induction, p38 activation itself is not sufficient to confer HO-1 expression and may not be involved in HO-1 and ICAM-1 induction in A549 cells.
authors.affiliation: Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College London, Heart Science Centre, Harefield Hospital, Harefield, UK.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Bundy
authors.forename: Ginette S
authors.initials: GS
authors.lastname: Hoare
authors.forename: Andrew
authors.initials: A
authors.lastname: Kite
authors.forename: Jessica
authors.initials: J
authors.lastname: Beach
authors.forename: Magdi
authors.initials: M
authors.lastname: Yacoub
authors.forename: Nándor
authors.initials: N
authors.lastname: Marczin
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005452:Fluoresceins / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000737:chemistry; D006454:Hemoglobins / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D016207:Cytokines; D004791:Enzyme Inhibitors; D005452:Fluoresceins; D006454:Hemoglobins; D007093:Imidazoles; D008565:Membrane Proteins; D016328:NF-kappa B; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D012402:Rotenone; D018799:Intercellular Adhesion Molecule-1; C037631:2',7'-dichlorofluorescein; D000493:Allopurinol; D000968:Antimycin A; D006427:Hemin; D006861:Hydrogen Peroxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D010100:Oxygen; D000111:Acetylcysteine