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Regulation of IL-1 Family Cytokines IL-1, IL-1 Receptor Antagonist, and IL-18 by 1,25-Dihydroxyvitamin D₃ in Primary Keratinocytes¹

Juan Kong^*, Sergei A. Grando and Yan Chun Li^2,*

^* Department of Medicine, University of Chicago, Chicago, IL 60637; and Department of Dermatology, University of California Davis Medical Center, Sacramento, CA 95817

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-1, 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-1 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-1 so that the ratio of icIL-1Ra to IL-1 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-1 and icIL-1Ra: it increased IL-1 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-1 ratio and suppressing IL-18 synthesis in keratinocytes.

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