Downregulation of interleukin 8 gene expression in human fibroblasts: Unique mechanism of transcriptional inhibition by interferon

The chemotactic cytokine interleukin 8 (IL-8) is produced upon stimulation by various agents in many cell types, including connective-tissue fibroblasts. Tumor necrosis factor (TNF) and IL-1 are potent inducers of IL-8 expression. Earlier we showed that TNF-induced stimulation of IL-8 mRNA accumulation in human FS-4 fibroblasts was inhibited by interferon β (IFN-β) or IFN-γ. Here we show that this inhibition is not specific for TNF, since IFN-β also reduced IL-8 mRNA accumulation induced by IL-1 or the double-stranded RNA poly (I·C). Treatment with IFN-γ also decreased TNF-induced IL-8 protein accumulation. Interestingly, the inhibitory effect was much less pronounced when IFN-β was added ≥1 hr before TNF. The inhibitory action of IFN-β on IL-8 mRNA accumulation was undiminished in the presence of inhibitors of protein synthesis. Nuclear run-on assays demonstrated that IFN-β caused a marked inhibition of TNF-induced IL-8 gene transcription; the transcriptional activation of several other TNF-induced genes was not inhibited by IFN-β. The results suggest that the specific inhibition of the transcriptional activation of IL-8 by IFN is due either to a transient inactivation of a factor required for IL-8 transcription or to the activation of a selective inhibitory factor.