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  • Title: TNF-alpha inhibits SP-A gene expression in lung epithelial cells via p38 MAPK.
    Author: Miakotina OL, Snyder JM.
    Journal: Am J Physiol Lung Cell Mol Physiol; 2002 Aug; 283(2):L418-27. PubMed ID: 12114204.
    Abstract:
    Surfactant protein A (SP-A), the major lung surfactant-associated protein, mediates local defense against pathogens and modulates inflammation in the alveolus. Tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine, inhibits SP-A gene expression in lung epithelial cells. Inhibitors of the phosphatidylinositol 3-kinase pathway, i.e., wortmannin, LY-294002, and rapamycin, did not block the inhibitory effects of TNF-alpha on SP-A mRNA levels. An inhibitor of the p44/42 mitogen-activated protein kinase (MAPK) pathway, PD-98059, was also ineffective. PD-169316 and SB-203580, inhibitors of p38 MAPK, blocked the TNF-alpha-mediated inhibition of SP-A mRNA levels. TNF-alpha increased the phosphorylation of p38 MAPK within 15 min. Anisomycin, an activator of p38 MAPK, increased p38 MAPK phosphorylation and decreased SP-A mRNA levels in a dose-dependent manner. Finally, TNF-alpha increased the phosphorylation of ATF-2, a transcription factor that is a p38 MAPK substrate. We conclude that TNF-alpha downregulates SP-A gene expression in lung epithelial cells via the p38 MAPK signal transduction pathway.
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