Regulation of the Egr-1 gene by tumor necrosis factor and interferons in primary human fibroblasts

J Biol Chem. 1992 Jan 15;267(2):1345-9.

Abstract

Treatment of quiescent primary human fibroblasts with tumor necrosis factor (TNF) alpha, TNF-beta, interleukin-1, interferon (IFN) alpha, IFN beta, or IFN gamma induced Egr-1 mRNA. In primary human fibroblasts TNF-alpha and TNF-beta were mildly mitogenic and IFN alpha and IFN gamma were growth inhibitory. However, in HeLa cells TNF but not IFN induced the expression of Egr-1 mRNA, while both cytokines inhibited HeLa cell division. Kinetic measurements of Egr-1 gene expression showed that TNF-alpha, TNF-beta, and IFN gamma increased the cellular concentration of Egr-1 mRNA within 30 min. A maximum induction of Egr-1 mRNA was detected at approximately 60 min which dropped to basal level by 180 min. Induction was inhibited by H7 and staurosporine but not by HA1004, indicating the involvement of a functional protein kinase C. The Egr-1 message was translated and the cellular Egr-1 protein detected within 60 min of cytokine treatment. Despite similar Egr-1 mRNA induction, the amount of Egr-1 protein translated in IFN alpha- and IFN gamma-treated cells was lower than in those treated with TNF-alpha and TNF-beta, and highest in the EGF-treated primary human fibroblasts. Indeed, the level of Egr-1 protein translated in these cells correlated proportionally with both the phosphorylation of cap-binding protein (eukaryotic initiation factor) and the amount of cellular DNA synthesis in the variously treated fibroblasts. These results suggest that both growth stimulatory and inhibitory cytokines can regulate Egr-1 gene expression at the transcriptional and translational level. However, the combination of these regulatory controls may determine the cellular concentration of the Egr-1 gene product and hence, its effect on cell proliferation.

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • 3T3 Cells
  • Alkaloids / pharmacology
  • Animals
  • Blotting, Northern
  • Blotting, Western
  • DNA / biosynthesis
  • Epidermal Growth Factor / pharmacology
  • Fibroblasts / drug effects
  • Gene Expression Regulation / drug effects*
  • HeLa Cells
  • Humans
  • Interferon-gamma / pharmacology*
  • Isoquinolines / pharmacology
  • Kinetics
  • Mice
  • Phosphorylation
  • Piperazines / pharmacology
  • RNA, Messenger / genetics
  • Staurosporine
  • Sulfonamides*
  • Thymidine / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Alkaloids
  • Isoquinolines
  • Piperazines
  • RNA, Messenger
  • Sulfonamides
  • Tumor Necrosis Factor-alpha
  • Epidermal Growth Factor
  • Interferon-gamma
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • DNA
  • N-(2-guanidinoethyl)-5-isoquinolinesulfonamide
  • Staurosporine
  • Thymidine