A role for TGFbeta signaling in the pathogenesis of psoriasis.

Deregulation of transforming growth factor-beta (TGFbeta) signaling has been reported in human psoriasis. Our recent study using a keratin 5 promoter (K5.TGFbeta1(wt)) showed that transgenic mice expressing wild-type TGFbeta1 in the epidermis developed severe skin inflammation. Additional experimental data further support a direct role for TGFbeta1 overexpression in skin inflammation. First, we temporally induced TGFbeta1 expression in keratinocytes in our gene-switch TGFbeta1(wt) transgenic mice and found inflammation severity correlated with TGFbeta1(wt) transgene expression. Second, deletion of T cells in K5.TGFbeta1(wt) mice significantly delayed skin inflammation and associated epidermal hyperplasia/hyperkeratosis. Third, therapeutic approaches effective for human psoriasis, that is, Etanercept and Rosiglitazone, are effective in alleviating the symptoms observed in K5.TGFbeta1(wt) mice. Future studies will analyze specific mechanisms and identify key factors in TGFbeta1-induced skin inflammation. Our mouse models will provide a useful tool for understanding the molecular mechanisms of inflammatory skin disorders in which TGFbeta1 is overexpressed.