DEXAMETHASONE SELECTIVELY REGULATES LPS-INDUCIBLE GENE-EXPRESSION IN MURINE PERITONEAL-MACROPHAGES

Our laboratory has recently described the characterization of three distinct cDNAs (designated C7, D3 and D8) encoding genes whose expression is induced in murine peritoneal macrophages by treatment with inflammatory stimuli such as IFNs and lipopolysaccharide (LPS). Sequence analysis of full-length cDNA for C7 suggests that this gene encodes the murine homologue of the human IFNγ-inducible protein IP-10. Partial sequence analysis of D3 and D8 cDNAs has revealed no significant homology with known sequences. Treatment of macrophages with the corticosteroid hormone dexamethasone (Dex) suppressed LPS-induced gene expression in a selective manner, having little or no effect on induced D3 mRNA levels, but markedly inhibiting the accumulation of both C7 and D8 mRNAs. The suppression of LPS-induced C7 and D8 mRNAs was dose-dependent in the range 0.01-10 μM Dex. Furthermore, the inhibitory effect was corticosteroid-specific because testosterone, β-estradiol and progesterone had no effect on gene expression when used at comparable dose. Inhibition of protein synthesis did not abolish the suppressive activity of Dex, indicating that no intermediate Dex-inducible protein was necessary to suppress the expression of LPS-inducible genes. When macrophages were treated with Dex after initiation of LPS treatment, the suppressive effects were diminished in a time-dependent fashion. However, even when the hormone was added as much as 2 h after LPS, sensitive gene expression was still markedly inhibited. Finally, Dex inhibited the transcription of genes encoding C7 and D8 mRNAs when administered 15 min before LPS but had little effect when added 1 h after LPS. The results indicate that the suppressive action of corticosteroid treatment on inflammatory gene expression in mononuclear phagocytes has both transcriptional and post-transcriptional components. © 1990.