1α,25‐Dihydroxyvitamin D₃ and a Variety of its Natural Metabolites Transcriptionally Repress Nuclear‐Factor‐κB‐Mediated Interleukin‐8 Gene Expression

Abstract

Regulation of interleukin-8 (IL-8) gene transcription occurs mainly through the sequences -94 to -71 of the 5'-flanking region of the IL-8 gene, involving the transcription factors nuclear factor for interleukin-6 (NF-IL-6) and nuclear factor KB (NF-KB). The human melanoma cell line A3 was derived from G-361 cells by stable transfection with an IL-8 promoter-luciferase construct containing these sequences. la,2S-Dihydroxyvitamin D, (calcitriol) repressed IL-8 promoter activity induced by tumor necrosis factor-a (TNF-a) by 50%, compared to 30% inhibition using dexamethasone, an effect consistent with its effect on TNF-a-induced IL-8 release and IL-8 mRNA levels. A variety of vitamin D metabolites caused the same repressive effect on IL-8 promoter activation as calcitriol. However, only those metabolites which were able to transactivate a classical vitamin D response element had the ability to repress IL-8 promoter activation, suggesting that this repression is mediated via vitamin D receptor (VDR). Furthermore, overexpression of VDR in the parental G-361 cell line enhanced the repressive effect of calcitriol on activation of the IL-8 promoter by either TNF-a stimulation or overexpression of the NF-KB subunit p65. Electrophoretic mobility shift assays using nuclear extracts from A3 cells showed that calcitriol decreased the abundance of nuclear factors bound to the NF-KB binding site of the IL-8 promoter and this reduced binding of NF-KB proteins presumably contributes to its inhibitory action.Keywords: interleukin-8 ; la,25-dihydroxyvitamin D, ; calcitriol ; regulation ; nuclear factor KB.The biologically active metabolite of vitamin D, the secosteroid hormone Ia,2S-dihydroxyvitamin D, (calcitriol), exerts profound effects on cellular differentiation and proliferation, bone mineralisation, calcium homeostasis, and immunomodulation. One mechanism by which calcitriol transduces its signals in target cells is binding to its nuclear receptor, the vitamin D receptor (VDR) (Baker et al., 1988). This receptor belongs to the superfamily of nuclear receptors, which includes steroid hormone receptors, thyroid hormone receptors, retinoic acid receptors (RAR), retinoid X receptors (RXR) and various orphan receptors with as yet undefined ligands. These receptors bind to specific DNA sequences, the hormone response elements, and act as ligand-inducible transcription factors. VDR, RARs, thyroid hormone receptors and peroxisome proliferator-activated receptor form heterodimers with the promiscuous partner RXR on their respective response elements (Yu et al., 1991 ;Kliewer et al., 1992;

Vitamin D supplementation guidelines

“…Vitamin D has shown a strong immunomodulatory capacity; high VDR levels have been reported in macrophages, dendritic cells, T lymphocytes, and B lymphocytes supports the conception of its fundamental role in combating bacteria, and preventing both autoimmune diseases and chronic inflammatory states (47)(48)(49)(50). The available evidence of extra-skeletal vitamin D actions and related health benefits is growing (5,7,9,.…”

Taq I polymorphism of the vitamin D receptor and risk of severe diabetic retinopathy

“…Moreover, it was found that topical administration of calcitriol can strongly reduce corneal neovascularization inhibiting leucocyte migration, and could also inhibit IL-1 alpha, IL-1 beta and IL-8 production by human corneal cells in vitro [31]. This could be partly because of its capacity to downregulate nuclear factor-kappa B [32]. Recently, one report Control group (n = 99) (Proliferative, n = 73 ; preproliferative DR, n = 28) (Absent, n = 32 ; background DR, n = 67)…”

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…The displacement of AP-1 leads to the inhibition of gene expression. Both RXR/VDR heterodimers and VDR monomers have been demonstrated to be involved in the inhibition (Alroy et al, 1995;Harant et al, 1997;Takeuchi et al, 2002).…”