Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: Role of neutrophils

Kiyoshi Takeyama, Karim Dabbagh, Jae Jeong Shim, Trang Dao-Pick, Iris F. Ueki, Jay A. Nadel

    Research output: Contribution to journalArticlepeer-review

    302 Citations (Scopus)

    Abstract

    Oxidative stress has been implicated in the pathogenesis of inflammatory diseases of airways. Here we show that oxidative stress causes ligand- independent activation of epidermal growth factor receptors (EGFR) and subsequent activation of nitogen-activated protein kinase kinase (MEK)-p44/42 mitogen-activated protein kinase (p44/42(mapk)), resulting in mucin synthesis in NCI-H292 cells. Exogenous hydrogen peroxide and neutrophils activated by IL-8, FMLP, or TNE-α increased EGFR tyrosine phophorylation and subsequent activation of p44/42(mapk) and up-regulated the expression of MUC5AC at both mRNA and protein levels in NCI-H292 cells. These effects were blocked by selective EGFR tyrosine kinase inhibitors (AG1478, BIBX1522) and by a selective MEK inhibitor (PD98059), whereas a selective platelet-derived growth factor receptor tyrosine kinase inhibitor (AG1295), a selective p38 MAPK inhibitor (SB203580), and a negative compound of tyrosine kinase inhibitors (A1) were without effect. Neutrophil supernatant-induced EGFR tyrosine phosphorylation, activation of p44/42(mapk), and MUC5AC synthesis were inhibited by antioxidants (N-acetyl-L-cysteine, DMSO, dimethyl thiourea, or superoxide dismutase); neutralizing Abs to EGFR ligands (EGF and TGF-α) were without effect, and no TGF-α protein was found in the neutrophil supernatant. In contrast, the EGFR ligand, TGF-α, increased EGFR tyrosine phosphorylation, activation of p44/42(mapk), and subsequent MUC5AC synthesis, but these effects were not inhibited by antioxidants. These results implicate oxidative stress in stimulating mucin synthesis in airways and provide new therapeutic approaches in airway hypersecretory diseases.

    Original languageEnglish
    Pages (from-to)1546-1552
    Number of pages7
    JournalJournal of Immunology
    Volume164
    Issue number3
    DOIs
    Publication statusPublished - 2000 Feb 1

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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