Departament de Farmacologia, Facultat de Farmàcia, Universitat de València, Valencia, Spain.
Exp Dermatol. 2013 May;22(5):323-8. doi: 10.1111/exd.12128.
Jak/Tyk proteins have recently aroused as possible therapeutic targets for the treatment of psoriasis. In psoriasis, these proteins signal through STAT molecules including STAT3, and STAT3 expression and activation has been shown augmented in psoriatic lesions. Here, we characterized the expression of Jak/Tyk proteins in lesional compared with non-lesional psoriatic skin. Jak1, Jak2 mRNA and protein and Tyk2 mRNA appeared to be downregulated, whereas Jak3 mRNA expression was increased. Moreover, STAT3 expression and activation was examined in psoriasis. STAT3 is activated at two phosphorylation sites: Tyr705 and Ser727. Both phosphorylation sites were phosphorylated in lesional psoriatic skin. The activation of STAT3 by Jak/Tyk proteins was studied in cultured normal human keratinocytes. Tyr705 phosphorylation was induced by IL-6 and IL-20 in a Jak2-dependent manner, and moreover, phosphorylation of Tyr705 produced a strong increase in STAT3 transcriptional activity. TNFα, 12-O-Tetradecanoylphorbol 13-acetate (TPA) and UVB irradiation induced Ser727 phosphorylation of STAT3 in an ERK1/2- and p38 MAPK-dependent manner, which resulted in a modulatory effect on STAT3 transcriptional activity. Our results demonstrate how different signalling pathways can integrate and lead to regulation of STAT3 transcriptional activity.
Jak/Tyk 蛋白最近被认为是治疗银屑病的潜在治疗靶点。在银屑病中，这些蛋白通过包括 STAT3 在内的 STAT 分子信号转导，并且已经表明 STAT3 在银屑病皮损中的表达和激活增强。在这里，我们比较了皮损和非皮损银屑病皮肤中 Jak/Tyk 蛋白的表达。Jak1、Jak2 mRNA 和蛋白以及 Tyk2 mRNA 似乎下调，而 Jak3 mRNA 表达增加。此外，还研究了 STAT3 在银屑病中的表达和激活。STAT3 在两个磷酸化位点：Tyr705 和 Ser727 被激活。磷酸化位点均在银屑病皮损中被磷酸化。研究了 Jak/Tyk 蛋白在培养的正常人角质形成细胞中对 STAT3 的激活。IL-6 和 IL-20 通过 Jak2 依赖性方式诱导 Tyr705 磷酸化，而且，Tyr705 的磷酸化导致 STAT3 转录活性的强烈增加。TNFα、12-O-十四烷酰佛波醇 13-乙酸酯（TPA）和 UVB 照射以 ERK1/2 和 p38 MAPK 依赖性方式诱导 STAT3 的 Ser727 磷酸化，这导致对 STAT3 转录活性的调节作用。我们的结果表明，不同的信号通路如何整合并导致 STAT3 转录活性的调节。
