Summary
Background
1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3), the active form of vitamin D, suppresses keratinocyte proliferation, promotes keratinocyte
differentiation, and induces involucrin expression. Peroxisome proliferation-activated
receptors (PPARs) are ligand-activated transcription factors. It has been reported
that PPARs stimulate keratinocyte differentiation and regulate the expression of differentiation
molecules.
Objective
Keratinocytes treated with 1α,25(OH)2D3 induced PPARγ, which was followed by increased involucrin expression. In this study,
we investigated whether PPARγ is involved in the 1α,25(OH)2D3-induced involucrin expression in human keratinocytes.
Methods
Subconfluent keratinocytes were treated with 10−7 M 1α,25(OH)2D3 for the indicated times, and PPAR and involucrin mRNA expression were determined
by real-time RT-PCR. The levels of PPARs, involucrin, p38, and phospho-p38 proteins
were assayed by Western blotting, and the DNA binding activities of PPARγ and AP-1
were investigated by electrophoretic mobility shift assays (EMSA). To examine the
role of PPARγ in 1α,25(OH)2D3 responses, recombinant adenovirus carrying a dominant-negative form of PPARγ (Axdn-PPARγ)
was constructed and transfected into keratinocytes. The p38 inhibitor SB203580 was
added to the cultures to evaluate the involvement of p38 in involucrin expression.
Results
1α,25(OH)2D3 induced PPARγ expression and stimulated PPARγ activity. The introduction of dn-PPARγ
inhibited the expression of involucrin mRNA and protein induced by 1α,25(OH)2D3, and suppressed AP-1 DNA binding activity. 1α,25(OH)2D3 also triggered the phosphorylation of p38, which contributes to involucrin induction.
Moreover, dn-PPARγ prevented the 1α,25(OH)2D3-induced phosphorylation of p38.
Conclusions
These results suggest that PPARγ regulates involucrin expression by controlling the
AP-1 signal and p38 activation in 1α,25(OH)2D3-induced keratinocyte differentiation.
Abbreviations:
1α,25(OH)2D3 (1α,25-dihydroxyvitamin D3), AP-1 (activator protein-1), Ax (adenovirus vector), m.o.i. (multiplicity of infection), PPAR (peroxisome proliferator-activated receptor), VDR (vitamin D receptor), VDRE (vitamin D response elements)Keywords
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Article info
Publication history
Published online: July 12, 2010
Accepted:
October 26,
2007
Received in revised form:
September 18,
2007
Received:
June 12,
2007
Identification
Copyright
© 2007 Japanese Society for Investigative Dermatology. Published by Elsevier Inc. All rights reserved.
