STAT1 expression and activation is increased in lesional psoriatic skin
STAT1 expression and activation is increased in lesional psoriatic skin
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DOI：
10.1111/bjd.12049
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发表时间：
2013-02-01
影响因子：
10.3
通讯作者：
Johansen, C.
中科院分区：
文献类型：
--
作者：
Hald, A.;Andres, R. M.;Johansen, C.
背景JAK（Janus kinase）/STAT（signal transducer and activator of transcription）信号通路在包括炎症在内的多种细胞过程中发挥重要作用。STAT 1的激活依赖于酪氨酸701和丝氨酸727磷酸化，这导致STAT二聚体的形成和STAT 1活性的调节，分别为目的确定STAT 1在银屑病皮肤中的表达和激活。定量聚合酶链反应检测STAT 1的mRNA表达，Western印迹检测STAT 1的蛋白表达和磷酸化水平。结果银屑病皮损中STAT 1的表达在mRNA和蛋白水平均显著增加，而在正常皮肤中STAT 1的表达则显著增加。此外，皮损中STAT 1（Tyr 701）和STAT 1（Ser 727）的磷酸化水平显著高于非皮损银屑病皮肤。荧光素酶测定显示，当用干扰素（IFN）-α或IFN-γ刺激培养的人角质形成细胞时，STAT 1诱导的转录活性显著诱导。在人角质形成细胞中，由IFN-α、IFN-γ或紫外线B诱导的STAT 1（Ser 727）磷酸化由蛋白激酶C（PKC）δ和p38丝裂原活化蛋白激酶依赖性机制介导，而IFN-α诱导的STAT 1（Tyr 701）磷酸化是由PKC-δ依赖性机制介导的。STAT 1（Ser 727）在银屑病皮损中表达增加。此外，导致这种磷酸化的特定信号通路已被确定。总之，我们的数据表明STAT 1在银屑病发病机制中的重要作用。
Background The JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling pathway is known to play an important role in many cellular processes including inflammation. The activation of STAT1 is dependent on tyrosine 701 and serine 727 phosphorylation, which leads to the formation of the STAT dimer and modulation of STAT1 activity, respectively.Objective To determine STAT1 expression and activation in psoriatic skin.Methods Biopsies were collected from patients with psoriasis. mRNA expression was evaluated by quantitative polymerase chain reaction, whereas the protein and phosphorylation level of STAT1 were evaluated by Western blotting. STAT1 localization was determined by immunofluorescence analysis and STAT1-induced transcriptional activity was analysed in cultured human keratinocytes using a reporter assay.Results The expression of STAT1 was demonstrated to be significantly increased at both mRNA and protein level in lesional psoriatic skin. In addition, the phosphorylation level of STAT1(Tyr701) and STAT1(Ser727) was significantly increased in lesional compared with nonlesional psoriatic skin. Luciferase assays showed a significant induction of the STAT1-induced transcriptional activity when cultured human keratinocytes were stimulated with either interferon (IFN)-alpha or IFN-gamma. STAT1(Ser727) phosphorylation induced by IFN-alpha, IFN-gamma or ultraviolet B was mediated by a protein kinase C (PKC) delta and p38 mitogen-activated protein kinase-dependent mechanism in human keratinocytes, whereas IFN-alpha-induced STAT1(Tyr701) phosphorylation was mediated by a PKC-delta-dependent mechanism.Conclusions This study demonstrates for the first time that the phosphorylation level of STAT1(Tyr701) and STAT1(Ser727) is increased in lesional psoriatic skin. In addition, specific signalling pathways leading to this phosphorylation have been identified. Together, our data indicate an important role of STAT1 in the pathogenesis of psoriasis.