Dermal fibroblasts are one of the therapeutic targets for topical application of 1 alpha,25-dihydroxyvitamin D-3: the possible involvement of transforming growth factor-beta induction

Background Transforming growth factor (TGF) -beta has been suggested to be an effective inhibitor for abnormal keratinocyte growth in psoriasis, As a majority of the secreted TGF-beta are biologically latent complexes, activa tion is essential for TGF-beta -mediated cellular responses in vitro and in vivo. Objectives Here we report the response of the TGF-beta regulation system to 1 alpha ,25-dihydroxyvitamin D-3-[1,25(OH)(2)D-3], an active vitamin D-3 a nalogue Patients/methods We studied two types of fibroblasts derived from normal an d psoriatic lesional skin, using an enzyme-linked immunosorbent assay and N orthern blotting techniques. Results 1,25(OH)(2)D-3 caused a dose-dependent induction of latent: and act ive TGF-beta1 proteins in both cell cultures. The increases were significan t over 72 h, but not within 48 h after stimulation. The time course of TGF- beta1 mRNA expression showed a biphasic response consisting of early (appro ximate to1 h) and late phases (approximate to 96 h) of induction. Concomita nt increases of TGF-beta2 and -beta3, other mammalian isoforms, were observ ed in the 1,25(OH)(2)D-3-treated cells, but the kinetics were all different . Coincubation with metabolic inhibitors, actinomycin D and cycloheximide, revealed that the early induction of TGF-beta1 mRNA by 1,25(OH)(2)D-3 is de pendent: 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-beta1 protein production. The late induction of TGF-bet a1 mRNA was partially blocked by adding isoform-specific antibodies to TGF- beta1, -beta2 and -beta3, indicating TGF-beta autoregulation. Despite these marked responses, there were no significant differences in the TGF-beta ex pression between normal and psoriatic fibroblasts. Conclusions These results suggest that antiproliferative and anti-inflammat ory effects of 1,25(OH)(2)D-3 on psoriatic lesional skin may be mediated, a t least in part, by a complex TGF-beta regulation in local dermal fibroblas ts.