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Transcriptional Regulation of Intracellular IL-1 Receptor Antagonist Gene by IL-1 in Primary Mouse Keratinocytes

Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957

The inflammatory cytokine IL-1 mediates inflammatory reactions in skin and up-regulates the expression of other proinflammatory genes. We previously found that IL-1 also increases steady state mRNA levels for intracellular IL-1 receptor antagonist (icIL-1Ra) in primary mouse keratinocytes; however, the mechanism for this was unknown. Here we show that increased expression in primary keratinocytes is due to increased rates of transcription. To study the transcriptional regulation of icIL-1Ra expression induced by IL-1, we functionally characterized 4.5 kb of the 5'-flanking region of the human icIL-1Ra gene. Deletion analysis showed that regulatory elements were contained in the -598- and -288-bp region upstream of the transcription start site. Then we investigated cis- and trans-acting factors required for icIL-1Ra expression and found that a NF-IL-6 site and a NF-B site in the icIL-1Ra promoter were responsible for IL-1-induced icIL-1Ra expression. Moreover, gel shift assays and cotransfection experiments showed that CCAAT/enhancer-binding proteins , , and p65 bind to the NF-IL-6 site and NF-B site, respectively, and functionally trans-activate the icIL-1Ra promoter. Finally, mutational analysis confirmed that these elements were both essential for maximal transcription induced by IL-1.

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