Downregulation of TGFβ isoforms and their receptors contributes to keratinocyte hyperproliferation in psoriasis vulgaris

Background: Psoriasis vulgaris is a chronic inflammatory disorder characterized by epidermal hyperproliferation. Transforming growth factor beta (TGFbetas) have a major anti proliferative action in epidermis. Objective: We evaluated the distribution and levels of expression of TGFbeta isoforms and their receptors in psoriatic versus normal skin with the goal of discovering potential alterations in TGFbeta signal transduction associated with psoriasis. Methods: Expression of TGFbeta isoforms and their receptors was analyzed in normal and psoriatic skin using immunohistochemistry, and reverse transcriptase-polymerase chain reaction (RT-PCR) techniques. Furthermore, DNA synthesis was measured in normal keratinocytes transfected with a dominant-negative TGFPbeta receptor II (TbetaRII) vector that eliminated most of the cytoplasmic TbetaRII domain. Results: Marked elevations in DNA synthesis, as assessed by BrdU incorporation and proliferating cell nuclear antigen (PCNA) immunoreactivity, were confirmed in psoriatic epithelial. cells. Using immunohistochemistry and RT-PCR analysis, expression of TGFbeta2 and 3 was diminished in the psoriatic epidermis as compared with those observed in normal skin. With respect to TGFP receptors, expression of TbetaRI and 11 was markedly decreased in the psoriatic epidermis. In addition, levels of Smad2 mRNA were also decreased in psoriatic skin. Transfection of normal keratinocytes with the dominant-negative TbetaRII vector significantly elevated DNA synthesis as compared with keratincoytes transfected with control vector (under condition of TGFbeta addition), suggesting that the dominant-negative TbetaRII mutant inhibits the antiproliferative effects of TGFbeta. Conclusion: The present investigation strongly suggest that the TGFbeta signaling pathway is downregulated in psoriatic skin and this situation leads to abnormal cell proliferation due to a functional decrease in growth regulation. (C) 2003 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.