TNF- inhibits SP-A gene expression in lung epithelial cells via p38 MAPK

Miakotina, Olga L., and Jeanne M. Snyder. TNFinhibits SP-A gene expression in lung epithelial cells via p38 MAPK. Am J Physiol Lung Cell Mol Physiol 283: L418–L427, 2002; 10.1152/ajplung.00470.2001.—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), 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 TNFon 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-mediated inhibition of SP-A mRNA levels. TNFincreased 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, TNFincreased the phosphorylation of ATF-2, a transcription factor that is a p38 MAPK substrate. We conclude that TNFdownregulates SP-A gene expression in lung epithelial cells via the p38 MAPK signal transduction pathway.