Tumor Necrosis Factor- Inhibits Surfactant Protein C Gene Transcription

doi:10.1074/jbc.270.33.19402

Tumor Necrosis Factor- Inhibits Surfactant Protein C Gene Transcription (*)

From the Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio 45229-3039

^¶ To whom correspondence should be addressed:
Children's Hospital Medical Center, Division of Pulmonary Biology, TCHRF, 3333 Burnet Ave., Cincinnati, OH 45229-3039.
Tel.: 513-559-4830; Fax: 513-559-7868.

↵^§ Present address: Dept. of Pediatrics, Strong Children's Medical Center, Rochester, NY 14642.

Abstract

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.

Footnotes

↵* This work was supported by Program in Molecular Biology Heart and Lung Grant HL40043, the Cystic Fibrosis Foundation, Training in Perinatal Biology Grant NRSA HD07200 (to C. J. B.), Training in Pulmonary and Cardiovascular Development Grant HL07752 (to S. E. K.), and National Institutes of Health Grant HL50046 (to S. W. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 The abbreviations used are:

ARDS

adult respiratory distress syndrome

TNF-α

tumor necrosis factor α

ICAM-1

intercellular adhesion molecule 1

rmTNF-α

recombinant mouse TNF-α

rhTNF-α

recombinant human TNF-α

TNF-R1

TNF-α receptor type 1

TNF-R2

TNF-αreceptor type 2

SP-A

SP-B, and SP-C, surfactant proteins A, B, and C

SV40 TAg

simian virus 40 large tumor antigen

CAT

chloramphenicol acetyltransferase

MLE

murine lung epithelial

bp

base pair(s)

kb

kilobase pair(s)

TTF-1

thyroid transcription factor 1.
↵²G. S. Pryhuber, unpublished observations.
↵³S. E. Kelly, C. J. Bachurski, and S. W. Glasser, unpublished observations.
- Received December 14, 1994.
- Revision received April 28, 1995.