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Dermal fibroblasts are one of the therapeutic targets for topical application of 1α,25-dihydroxyvitamin D3: the possible involvement of transforming growth factor-β induction

Authors


Fumio Kaneko, MD, PhD. E-mail: kaneko@fmu.ac.jp

Abstract

Background Transforming growth factor (TGF) -β has been suggested to be an effective inhibitor for abnormal keratinocyte growth in psoriasis. As a majority of the secreted TGF-β are biologically latent complexes, activation is essential for TGF-β-mediated cellular responses in vitro and in vivo.

Objectives Here we report the response of the TGF-β regulation system to 1α,25-dihydroxyvitamin D3[1,25(OH)2D3], an active vitamin D3 analogue

Patients/methods We studied two types of fibroblasts derived from normal and psoriatic lesional skin, using an enzyme-linked immunosorbent assay and Northern blotting techniques.

Results 1,25(OH)2D3 caused a dose-dependent induction of latent and active TGF-β1 proteins in both cell cultures. The increases were significant over 72 h, but not within 48 h after stimulation. The time course of TGF-β1 mRNA expression showed a biphasic response consisting of early (≈1 h) and late phases (≈ 96 h) of induction. Concomitant increases of TGF-β2 and -β3, other mammalian isoforms , were observed in the 1,25(OH)2D3-treated cells, but the kinetics were all different. Co-incubation with metabolic inhibitors, actinomycin D and cycloheximide, revealed that the early induction of TGF-β1 mRNA by 1,25(OH)2D3 is dependent on de novo RNA synthesis, but not on RNA stabilization or protein synthesis. It seems likely to be a transient and negligible response given the absence of TGF-β1 protein production. The late induction of TGF-β1 mRNA was partially blocked by adding isoform-specific antibodies to TGF-β1, -β2 and -β3, indicating TGF-β autoregulation. Despite these marked responses, there were no significant differences in the TGF-β expression between normal and psoriatic fibroblasts.

Conclusions These results suggest that antiproliferative and anti-inflammatory effects of 1,25(OH)2D3 on psoriatic lesional skin may be mediated, at least in part, by a complex TGF-β regulation in local dermal fibroblasts.

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