Tumor Necrosis Factor-α Inhibits Surfactant Protein C Gene Transcription

Pulmonary surfactant protein C (SP-C) is a 3.7-kDa, hydrophobic peptide secreted by alveolar type II epithelial cells. SP-C enhances surface tension lowering activity of surfactant phospholipids that is critical to the maintenance of alveolar volume at end expiration. The proinflammatory cytokine, tumor necrosis factor α (TNF-α), decreased SP-C mRNA within 24 h of intratracheal administration to mice. In vitro, TNF-α 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 contrast, TNF-α induced intercellular adhesion molecule-1 expression in both mouse lung and murine lung epithelial cell lines. Nuclear run-on analysis demonstrated that transcription of both the endogenous SP-C gene and a human SP-C promoter-driven transgene was inhibited by TNF-α. TNF-α decreased mouse SP-C-chloramphenicol acetyltransferase mRNA in stably transfected murine lung epithelial cells. Deletion analysis of the SP-C promoter region demonstrated that TNF-α inhibited gene expression in constructs containing 320 base pairs 5′ from the start of transcription of the mouse SP-C gene. Inhibition of surfactant protein C gene transcription by TNF-α may contribute to the abnormalities of surfactant homeostasis associated with pulmonary injury and infection. Pulmonary surfactant protein C (SP-C) is a 3.7-kDa, hydrophobic peptide secreted by alveolar type II epithelial cells. SP-C enhances surface tension lowering activity of surfactant phospholipids that is critical to the maintenance of alveolar volume at end expiration. The proinflammatory cytokine, tumor necrosis factor α (TNF-α), decreased SP-C mRNA within 24 h of intratracheal administration to mice. In vitro, TNF-α 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 contrast, TNF-α induced intercellular adhesion molecule-1 expression in both mouse lung and murine lung epithelial cell lines. Nuclear run-on analysis demonstrated that transcription of both the endogenous SP-C gene and a human SP-C promoter-driven transgene was inhibited by TNF-α. TNF-α decreased mouse SP-C-chloramphenicol acetyltransferase mRNA in stably transfected murine lung epithelial cells. Deletion analysis of the SP-C promoter region demonstrated that TNF-α inhibited gene expression in constructs containing 320 base pairs 5′ from the start of transcription of the mouse SP-C gene. Inhibition of surfactant protein C gene transcription by TNF-α may contribute to the abnormalities of surfactant homeostasis associated with pulmonary injury and infection.