Studies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3-Ser727 phosphorylation as a modulator of transcriptional activity

被引:104
作者
Andres, Rosa M. [1 ]
Hald, Anne [2 ]
Johansen, Claus [2 ]
Kragballe, Knud [2 ]
Iversen, Lars [2 ]
机构
[1] Univ Valencia, Fac Farm, Dept Farmacol, E-46010 Valencia, Spain
[2] Aarhus Univ Hosp, Dept Dermatol, DK-8000 Aarhus C, Denmark
基金
英国医学研究理事会;
关键词
IL-20; IL-6; Jak proteins; psoriasis; STAT3; SERINE PHOSPHORYLATION; STAT3; INHIBITION; TYROSINE; IL-20; SKIN; INTERLEUKIN-6; INFLAMMATION; ACTIVATION; EPIDERMIS;
D O I
10.1111/exd.12128
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
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. TNF, 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.
引用
收藏
页码:323 / 328
页数:6
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