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.

KEYWORDS:

• c-Jun N-terminal kinase
• calcitriol
• keratinocytes
• tumor necrosis factor
• vitamin D receptor

Abbreviations

CYP24A1	=	1,25-dihydroxyvitamin D3 24-hydroxylase
IL-1β	=	interleukin-1β
IFNγ	=	interferon γ
JNK	=	c-Jun N-terminal kinase
TNF	=	tumor necrosis factor α
VDR	=	vitamin D receptor

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was performed in partial fulfillment of the requirements for a Ph.D. degree of Ester Ziv, Sackler Faculty of Medicine, Tel Aviv University, Israel.