Doi Hisao, Shibata Masa-Aki, Kiyokane Kimihiro, Otsuki Yoshinori
Department of Dermatology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
J Dermatol Sci. 2003 Oct;33(1):7-16. doi: 10.1016/s0923-1811(03)00107-5.
Psoriasis vulgaris is a chronic inflammatory disorder characterized by epidermal hyperproliferation. Transforming growth factor beta (TGFbetas) have a major antiproliferative action in epidermis.
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.
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 TGFbeta receptor II (TbetaRII) vector that eliminated most of the cytoplasmic TbetaRII domain.
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 TGFbeta receptors, expression of TbetaRI 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 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.
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.
寻常型银屑病是一种以表皮过度增殖为特征的慢性炎症性疾病。转化生长因子β（TGFβs）在表皮中具有主要的抗增殖作用。
我们评估了TGFβ亚型及其受体在银屑病皮肤与正常皮肤中的分布和表达水平，目的是发现与银屑病相关的TGFβ信号转导的潜在改变。
使用免疫组织化学和逆转录聚合酶链反应（RT-PCR）技术分析正常皮肤和银屑病皮肤中TGFβ亚型及其受体的表达。此外，在转染了显性负性TGFβ受体II（TβRII）载体的正常角质形成细胞中测量DNA合成，该载体消除了大部分细胞质TβRII结构域。
通过BrdU掺入和增殖细胞核抗原（PCNA）免疫反应性评估，银屑病上皮细胞中的DNA合成明显升高。使用免疫组织化学和RT-PCR分析，与正常皮肤相比，银屑病表皮中TGFβ2和3的表达减少。关于TGFβ受体，银屑病表皮中TβRI和II的表达明显降低。此外，银屑病皮肤中Smad2 mRNA水平也降低。与转染对照载体的角质形成细胞相比，用显性负性TβRII载体转染正常角质形成细胞在添加TGFβ的条件下显著提高了DNA合成，表明显性负性TβRII突变体抑制了TGFβ的抗增殖作用。
本研究强烈表明，银屑病皮肤中TGFβ信号通路下调，这种情况由于生长调节功能下降导致细胞增殖异常。
