TUMOR-NECROSIS-FACTOR-ALPHA INHIBITS SURFACTANT PROTEIN-C GENE-TRANSCRIPTION

Pulmonary surfactant protein C (SP-C) is a 3.7-kDa, hydrophobic peptid e secreted by alveolar type II epithelial cells. SP-C enhances surface tension lowering activity of surfactant phospholipids that is critica l to the maintenance of alveolar volume at end expiration. The proinfl ammatory cytokine, tumor necrosis factor alpha (TNF-alpha), decreased SP-C mRNA within 24 h of intratracheal administration to mice. In vitr o, TNF-alpha decreased SP-C mRNA in a time- and dose-dependent manner, reducing the steady state levels of SP-C mRNA by 3-5-fold. In contras t, TNF-alpha induced intercellular adhesion molecule-1 expression in b oth mouse lung and murine lung epithelial cell lines. Nuclear run-on a nalysis demonstrated that transcription of both the endogenous SP-C ge ne and a human SP-C promoter-driven transgene was inhibited by TNF-alp ha. TNF-alpha decreased mouse SP-C chloramphenicol acetyltransferase m RNA in stably transfected murine lung epithelial cells, Deletion analy sis of the SP-C promoter region demonstrated that TNF-alpha inhibited gene expression in constructs containing 320 base pairs 5' from the st art of transcription of the mouse SP-C gene. Inhibition of surfactant protein C gene transcription by TNF-alpha may contribute to the abnorm alities of surfactant homeostasis associated with pulmonary injury and infection.