Regulation of IL-1 Family Cytokines IL-1α, IL-1 Receptor Antagonist, and IL-18 by 1,25-Dihydroxyvitamin D3 in Primary Keratinocytes

Abstract

IL-1 family cytokines are key mediators of inflammatory response. Excessive production of these cytokines by keratinocytes has been implicated in inflammatory and hyperproliferative skin diseases. Given the immunosuppressive role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its clinical application in treatment of psoriasis, we investigated the effect of 1,25(OH)2D3 on the expression of IL-1α, intracellular IL-1 receptor antagonist (icIL-1Ra), and IL-18 in mouse primary keratinocytes. Treatment of keratinocytes with 1,25(OH)2D3 increased the expression of IL-1α and icIL-1Ra and decreased the expression of IL-18 in dose- and time-dependent manners. The magnitude of icIL-1Ra induction was much greater than that of IL-1α so that the ratio of icIL-1Ra to IL-1α was markedly increased, leading to repression of IL-1 activity. The regulation of these three cytokines by 1,25(OH)2D3 was mediated by vitamin D receptor (VDR), as 1,25(OH)2D3 had no effect in VDR−/− keratinocytes, whereas the effect was restored in cells derived from VDR−/− mice expressing human VDR. 1,25(OH)2D3 appeared to use different mechanisms to regulate the biosynthesis of IL-1α and icIL-1Ra: it increased IL-1α mRNA stability whereas it enhanced icIL-1Ra gene transcription. The basal IL-18 expression and activity were much higher in VDR−/− keratinocytes and skin, underscoring the importance of the repressive role of vitamin D in IL-18 production. Similar regulation of these cytokines was also seen in primary human keratinocytes. Collectively, these results suggest that vitamin D modulates cutaneous inflammatory reactions, at least in part, by increasing the IL-1Ra to IL-1α ratio and suppressing IL-18 synthesis in keratinocytes.