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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

JNK pathway is partially involved in the upregulation of VDR by TNF. HaCaT cells were treated with SP600125 (SP) (30 μM), SB203580 (SB) (5 μM), U0126 (1 μM) or BMS345541 (BMS) (1 μM) for 30 minutes and then exposed to TNF (10 ng/mL) in the presence of inhibitors for 24 hours. VDR protein levels were determined in cell extracts by protein gel blot analysis (A) and mRNA levels of VDR were quantified by real-time PCR and normalized to RPLP0 mRNA levels (B,C). Data are presented as mean ± SD of four independent cultures. The significance of the difference between groups was assessed by unpaired Student's t-test: cultures treated vs non-treated with TNF (*, P < 0.05); cultures treated vs non-treated with inhibitor (#, P < 0.05).
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f0004: JNK pathway is partially involved in the upregulation of VDR by TNF. HaCaT cells were treated with SP600125 (SP) (30 μM), SB203580 (SB) (5 μM), U0126 (1 μM) or BMS345541 (BMS) (1 μM) for 30 minutes and then exposed to TNF (10 ng/mL) in the presence of inhibitors for 24 hours. VDR protein levels were determined in cell extracts by protein gel blot analysis (A) and mRNA levels of VDR were quantified by real-time PCR and normalized to RPLP0 mRNA levels (B,C). Data are presented as mean ± SD of four independent cultures. The significance of the difference between groups was assessed by unpaired Student's t-test: cultures treated vs non-treated with TNF (*, P < 0.05); cultures treated vs non-treated with inhibitor (#, P < 0.05).

Mentions: By using an inhibitor of the c-Jun N-terminal kinase (JNK), SP600125, we found that this pathway is involved in the up regulation of VDR by TNF as evidenced both on the protein and mRNA levels (Fig. 4A-B). Using pharmacological inhibitors (SB203580 and BMS345541) of other signaling pathways we found that the p38 MAPK and the NFκB signaling pathways are not involved in the upregulation of VDR by TNF. The inhibitor of the ERK pathway, U0126, moderately increased the effect of TNF, indicating that the ERK pathway exerts an inhibitory effect on the upregulation of VDR by TNF (Fig. 4C).Figure 4.


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)

JNK pathway is partially involved in the upregulation of VDR by TNF. HaCaT cells were treated with SP600125 (SP) (30 μM), SB203580 (SB) (5 μM), U0126 (1 μM) or BMS345541 (BMS) (1 μM) for 30 minutes and then exposed to TNF (10 ng/mL) in the presence of inhibitors for 24 hours. VDR protein levels were determined in cell extracts by protein gel blot analysis (A) and mRNA levels of VDR were quantified by real-time PCR and normalized to RPLP0 mRNA levels (B,C). Data are presented as mean ± SD of four independent cultures. The significance of the difference between groups was assessed by unpaired Student's t-test: cultures treated vs non-treated with TNF (*, P < 0.05); cultures treated vs non-treated with inhibitor (#, P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f0004: JNK pathway is partially involved in the upregulation of VDR by TNF. HaCaT cells were treated with SP600125 (SP) (30 μM), SB203580 (SB) (5 μM), U0126 (1 μM) or BMS345541 (BMS) (1 μM) for 30 minutes and then exposed to TNF (10 ng/mL) in the presence of inhibitors for 24 hours. VDR protein levels were determined in cell extracts by protein gel blot analysis (A) and mRNA levels of VDR were quantified by real-time PCR and normalized to RPLP0 mRNA levels (B,C). Data are presented as mean ± SD of four independent cultures. The significance of the difference between groups was assessed by unpaired Student's t-test: cultures treated vs non-treated with TNF (*, P < 0.05); cultures treated vs non-treated with inhibitor (#, P < 0.05).
Mentions: By using an inhibitor of the c-Jun N-terminal kinase (JNK), SP600125, we found that this pathway is involved in the up regulation of VDR by TNF as evidenced both on the protein and mRNA levels (Fig. 4A-B). Using pharmacological inhibitors (SB203580 and BMS345541) of other signaling pathways we found that the p38 MAPK and the NFκB signaling pathways are not involved in the upregulation of VDR by TNF. The inhibitor of the ERK pathway, U0126, moderately increased the effect of TNF, indicating that the ERK pathway exerts an inhibitory effect on the upregulation of VDR by TNF (Fig. 4C).Figure 4.

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