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Mechanism of IFN--Mediated Inhibition of IL-8 Gene Expression in Astroglioma Cells¹

Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294

IL-8 is a chemokine that recruits migrating neutrophils and leukocytes to areas of inflammation. In noninflamed tissue, IL-8 expression is low but can be rapidly induced by proinflammatory cytokines. Typically, inflammation and transient IL-8 expression are beneficial. However, some diseases are characterized by excessive inflammation and high levels of IL-8. Previous studies have shown that IFN- can inhibit the expression of IL-8, although the mechanism is unknown. Using chromatin immunoprecipitation assays, we define the IL-8 transcriptional program in the absence or presence of inducing stimuli and/or inhibition by IFN-. In the absence of stimuli, the IL-8 promoter is acetylated but negatively regulated by corepressor proteins. Upon PMA stimulation, the levels of these corepressors are reduced and the promoter is rapidly bound and activated by transcription factors, including NF-B p65, C/EBP, and c-Fos. In addition, RNA polymerase II is recruited to the IL-8 promoter to initiate transcription. However, in the presence of both PMA and IFN-, there are diminished levels of histone acetylation, reduced levels of transcription factors such as NF-B p65 and RNA polymerase II, and an increased presence of corepressor proteins such as histone deacetylases 1 and 3 and silencing mediator of retinoic acid and thyroid hormone receptors. IFN--inducible protein-10 and MCP-1 genes, also regulated by NF-B, are unaffected by IFN-, and IFN- does not prevent the activation, nuclear migration, or binding of NF-B p65 to the B element of the IFN--inducible protein-10 promoter. As such, these data show that the inhibitory effects of IFN- are specific to the IL-8 promoter.

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