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

Authors
Journal
Journal of Dermatological Science
0923-1811
Publisher
Elsevier
Publication Date
Volume
33
Issue
1
Identifiers
DOI: 10.1016/s0923-1811(03)00107-5
Keywords
  • Tgfβ
  • Tgfβ Receptors
  • Psoriasis
  • A Dominant-Negative Tgfβ Type Ii Receptor
Disciplines
  • Chemistry

Abstract

Abstract Background: Psoriasis vulgaris is a chronic inflammatory disorder characterized by epidermal hyperproliferation. Transforming growth factor β (TGFβs) have a major antiproliferative action in epidermis. Objective: We evaluated the distribution and levels of expression of TGFβ isoforms and their receptors in psoriatic versus normal skin with the goal of discovering potential alterations in TGFβ signal transduction associated with psoriasis. Methods: Expression of TGFβ 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 TGFβ receptor II (TβRII) vector that eliminated most of the cytoplasmic TβRII 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 TGFβ2 and 3 was diminished in the psoriatic epidermis as compared with those observed in normal skin. With respect to TGFβ receptors, expression of TβRI and II 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 TβRII vector significantly elevated DNA synthesis as compared with keratincoytes transfected with control vector (under condition of TGFβ addition), suggesting that the dominant-negative TβRII mutant inhibits the antiproliferative effects of TGFβ. Conclusion: The present investigation strongly suggest that the TGFβ signaling pathway is downregulated in psoriatic skin and this situation leads to abnormal cell proliferation due to a functional decrease in growth regulation.

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