Differential contribution of IL-1Ra isoforms to allele-specific IL-1Ra mRNA accumulation

The interleukin-1 (IL-1) receptor antagonist (IL-1Ra) gene produces two isoforms of IL-1Ra, intracellular (icIL-1Ra) and secreted (sIL-1Ra). Distinct promoter regions control synthesis of each isoform. Five alleles of this gene, defined by sIL-1Ra intron 2 polymorphism, have been described. Although differences in IL-1Ra protein production have been demonstrated in various tissues and cells obtained from individuals carrying allele 1 vs. allele 2, the underlying mechanisms of this discrepancy remain poorly understood. We hypothesize that one mechanism contributing to differences in protein levels may be allele-specific accumulation of icIL-1Ra or sIL-1Ra mRNA. Quantification of allele-specific differences in mRNA accumulation in colonic biopsies and peripheral blood mononuclear cells (PBMC) of heterozygous individuals shows that the amount of allele 1-specific icIL-1Ra mRNA averaged four times higher relative to allele 2. In transfection assays, gene expression directed by the allele 1-specific icIL-1Ra promoter fragment was found to be greater than that directed by the allele 2 promoter, suggesting that icIL-1Ra promoter activity contributes to the disparity in the allele-specific icIL-1Ra mRNA accumulation. Our data show that differences in the transcriptional regulation of icIL-1Ra alleles 1 and 2 may be involved in the production of icIL-1Ra protein. Disregulated icIL-1Ra production may play a role in chronic inflammatory diseases where the balance between IL-1 and IL-1Ra has been implicated as a key pathogenic mechanism.