TNF-α increases the expression and activity of vitamin D receptor in keratinocytes: role of c-Jun N-terminal kinase

Abstract

Several inflammatory mediators increase calcitriol production by epidermal keratinocytes. In turn calcitriol attenuates the keratinocyte inflammatory response. Since the effect of the in-situ generated calcitriol depends also on the sensitivity to the hormone we studied the effect of inflammatory cytokines on the response of HaCaT human keratinocytes to calcitriol by examining the expression and transcriptional activity of VDR. Treatment with TNF, but not with IL-1β or interferon γ, increased VDR protein level, while decreasing the level of its heterodimerization partner RXRα. This was associated with increased VDR mRNA levels. c-Jun N-terminal kinase, but not P38 MAPK or NFκB, was found to participate in the upregulation of VDR by TNF. The functional significance of the modulation of VDR and RXRα levels by TNF is manifested by increased induction of VDR target gene CYP24A1 by calcitriol. Calcitriol, in turn, inhibited the enhanced expression of VDR by TNF. In conclusion, the inflammatory cytokine TNF increases the response of keratinocytes to calcitriol through upregulation of its receptor VDR, which in turn is subject to negative feedback by the hormone accelerating the return of the keratinocyte vitamin D system to its basal activity. We surmise that the increased generation and sensitivity to calcitriol in keratinocytes play a role in the resolution of epidermal inflammation.

Adipose tissue inflammation and VDR expression and methylation in colorectal cancer

“…These high VDR levels in adipose tissue might be due to a compensatory mechanism in response to the low 25(OH)D levels in these subjects, and it could be a sign of VD insufficiency. Moreover, it has been reported that the inflammatory factor TNF can activate VDR gene expression [ 50 ]. So, a lack of 25(OH)D might lead to an inflammatory process which could subsequently promote VDR expression as we observed in our study.…”

Current therapies in alleviating liver disorders and cancers with a special focus on the potential of vitamin D

“…Many other cell types like the pancreas skin, vasculature, colon and immune system cells expressing VDR may also produce extra-renal 1,25(OH)2D3 [ 14 , 61 ]. It has been observed that TNF alpha enhances the responsiveness of keratinocytes toward production of calcitriol, by upregulating VDR receptor through increased m RNA levels [ 62 ].…”

The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights

“…The selective presence of the VDR in specific cell types supports the idea that expression from the VDR gene itself is uniquely regulated. Accordingly, there is evidence for VDR transcriptional modulation through multiple signaling pathways in different cell types (28)(29)(30), including its regulation in immune cells by TLRs (25). Nevertheless, a re-assessment of many of the earlier findings of the mechanisms associated with VDR gene regulation is now underway due to results from recent genomewide studies using ChIP deep sequencing (ChIP-seq) and other analyses.…”