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

Ziv E, Koren R, Zahalka MA, Ravid A - Dermatoendocrinol (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Basil and Gerald Felsenstein Medical Research Center, Beilinson Campus, Petah Tikva, Israel; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

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.

No MeSH data available.


Related in: MedlinePlus

TNF increases CYP24A1 gene expression induced by calcitriol. HaCaT cells were treated with TNF (10 ng/mL) for 22 hours. Calcitriol was then added to TNF-treated and untreated cultures for 2 hours. mRNA levels of CYP24A1 were quantified by real-time PCR and normalized to RPLP0 mRNA levels. Values for untreated cultures were assigned the arbitrary value of 1. The significance of the difference between groups was assessed by unpaired Student's t-test: cultures treated vs non-treated with calcitriol (*, P < 0.01); cultures treated vs non-treated with TNF (#, P < 0.01).
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f0003: TNF increases CYP24A1 gene expression induced by calcitriol. HaCaT cells were treated with TNF (10 ng/mL) for 22 hours. Calcitriol was then added to TNF-treated and untreated cultures for 2 hours. mRNA levels of CYP24A1 were quantified by real-time PCR and normalized to RPLP0 mRNA levels. Values for untreated cultures were assigned the arbitrary value of 1. The significance of the difference between groups was assessed by unpaired Student's t-test: cultures treated vs non-treated with calcitriol (*, P < 0.01); cultures treated vs non-treated with TNF (#, P < 0.01).

Mentions: The opposing effects of TNF on VDR and its heterodimerization partner RXRα leaves unpredictable its impact on VDR ligand activity. The functional significance of these opposing effects was assessed by assaying VDR transcriptional activity (e.g., induction of its target gene, CYP24A1) in control and TNF-treated cells following exposure to calcitriol. As can been seen in Figure 3, 22 hour treatment with TNF increased the responsiveness of HaCaT cells to calcitriol as determined by induction of CYP24A1.Figure 3.


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

Ziv E, Koren R, Zahalka MA, Ravid A - Dermatoendocrinol (2016)

TNF increases CYP24A1 gene expression induced by calcitriol. HaCaT cells were treated with TNF (10 ng/mL) for 22 hours. Calcitriol was then added to TNF-treated and untreated cultures for 2 hours. mRNA levels of CYP24A1 were quantified by real-time PCR and normalized to RPLP0 mRNA levels. Values for untreated cultures were assigned the arbitrary value of 1. The significance of the difference between groups was assessed by unpaired Student's t-test: cultures treated vs non-treated with calcitriol (*, P < 0.01); cultures treated vs non-treated with TNF (#, P < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4862379&req=5

f0003: TNF increases CYP24A1 gene expression induced by calcitriol. HaCaT cells were treated with TNF (10 ng/mL) for 22 hours. Calcitriol was then added to TNF-treated and untreated cultures for 2 hours. mRNA levels of CYP24A1 were quantified by real-time PCR and normalized to RPLP0 mRNA levels. Values for untreated cultures were assigned the arbitrary value of 1. The significance of the difference between groups was assessed by unpaired Student's t-test: cultures treated vs non-treated with calcitriol (*, P < 0.01); cultures treated vs non-treated with TNF (#, P < 0.01).
Mentions: The opposing effects of TNF on VDR and its heterodimerization partner RXRα leaves unpredictable its impact on VDR ligand activity. The functional significance of these opposing effects was assessed by assaying VDR transcriptional activity (e.g., induction of its target gene, CYP24A1) in control and TNF-treated cells following exposure to calcitriol. As can been seen in Figure 3, 22 hour treatment with TNF increased the responsiveness of HaCaT cells to calcitriol as determined by induction of CYP24A1.Figure 3.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Basil and Gerald Felsenstein Medical Research Center, Beilinson Campus, Petah Tikva, Israel; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

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.

No MeSH data available.


Related in: MedlinePlus