title: Regulation of IL-1 family cytokines IL-1alpha, 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 D(3) (1,25(OH)(2)D(3)) and its clinical application in treatment of psoriasis, we investigated the effect of 1,25(OH)(2)D(3) on the expression of IL-1alpha, intracellular IL-1 receptor antagonist (icIL-1Ra), and IL-18 in mouse primary keratinocytes. Treatment of keratinocytes with 1,25(OH)(2)D(3) increased the expression of IL-1alpha 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-1alpha so that the ratio of icIL-1Ra to IL-1alpha was markedly increased, leading to repression of IL-1 activity. The regulation of these three cytokines by 1,25(OH)(2)D(3) was mediated by vitamin D receptor (VDR), as 1,25(OH)(2)D(3) had no effect in VDR(-/-) keratinocytes, whereas the effect was restored in cells derived from VDR(-/-) mice expressing human VDR. 1,25(OH)(2)D(3) appeared to use different mechanisms to regulate the biosynthesis of IL-1alpha and icIL-1Ra: it increased IL-1alpha 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-1alpha ratio and suppressing IL-18 synthesis in keratinocytes.
authors.affiliation: Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Kong
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Grando
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Li
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010703:Phorbol Esters / Q000494:pharmacology; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D020382:Interleukin-18; D010703:Phorbol Esters; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D012795:Sialoglycoproteins; D002117:Calcitriol; D002118:Calcium