Tumor necrosis factor-alpha 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 alpha (TNF-alpha), decreased SP-C mRNA within 24 h of intratracheal administration to mice. In vitro, 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 contrast, TNF-alpha 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-alpha. TNF-alpha decreased mouse SP-C chloramphenicol acetyltransferase mRNA in stably transfected murine epithelial cells. Deletion analysis of the SP-C promoter region demonstrated that TNF-alpha 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-alpha may contribute to the abnormalities of surfactant homeostasis associated with pulmonary injury and infection.
Bachurski
C J
CJ
Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio 45229-3039, USA.
Pryhuber
G S
GS
Glasser
S W
SW
Kelly
S E
SE
Whitsett
J A
JA
D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D011510:Proteolipids / Q000235:genetics*; D011663:Pulmonary Surfactants / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D011510:Proteolipids; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha