Transcriptional and posttranscriptional regulation of macrophage-specific colony stimulating factor gene expression by tumor necrosis factor. Involvement of arachidonic acid metabolites.

Open Access
Publisher Website
Google Scholar
Abstract
The effects of tumor necrosis factor (TNF) on the regulation of macrophage-specific colony stimulating factor (CSF-1) gene expression have been studied in HL-60 cells during monocytic differentiation. CSF-1 transcripts were undetectable in uninduced HL-60 cells, reached maximal levels by 3 h of exposure to TNF, and returned to that of control cells by 24 h. Transcriptional run-on analysis demonstrated that exposure to TNF stimulated the rate of CSF-1 gene transcription by 6.4-fold. The combination of a protein synthesis inhibitor, cycloheximide, and TNF increased levels of CSF-1 mRNA compared with treatment by TNF alone. We also studied the signal transduction mechanisms responsible for regulating TNF-induced CSF-1 mRNA levels. Both 4-bromophenacyl bromide and quinacrine, inhibitors of phospholipase A2 activity, blocked TNF-induced increases in CSF-1 transcripts in a concentration-dependent manner, while caffeic acid and nordihydroguaiaretic acid, inhibitors of the 5-lipoxygenase pathway, had no detectable effect on induction of CSF-1 RNA. PGE2 or dibutyryl cAMP treatment of HL-60 cells in the presence of TNF blocked the expression of CSF-1 mRNA in a dose-dependent manner. These findings suggest that the increase in CSF-1 RNA observed during TNF treatment is regulated, at least in part, by both transcriptional and posttranscriptional mechanisms, and that PGE2 and cAMP regulate transcriptional activation of the CSF-1 gene by TNF.

This publication has 38 references indexed in Scilit: