期刊
BRITISH JOURNAL OF DERMATOLOGY
卷 182, 期 1, 页码 119-129出版社
OXFORD UNIV PRESS
DOI: 10.1111/bjd.17940
关键词
-
类别
资金
- Deutsche Forschungsgemeinschaft [WO-541/13-2]
Background Thymic stromal lymphopoietin (TSLP) mediates proallergic T helper 2-type responses by acting on leucocytes. Endogenous pathways regulating TSLP production are poorly defined. Objectives To uncover the mechanisms by which skin barrier disruption elicits TSLP production and to delineate the level at which individual mechanistic components may converge. Methods A combination of primary keratinocytes, skin explants and in vivo strategies was employed. Murine skin was tape stripped in the presence of neutralizing antibodies or antagonists. Cells and explants were stimulated with interleukin (IL)-1 and protease-activated receptor 2 agonist (PAR-2-Ag). TSLP levels were quantified by enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction. Chromatin immunoprecipitation and promoter reporter assays were used to examine recruitment and functional activity of nuclear factor kappa B (NF-kappa B) at the TSLP promoter. Results TSLP induction in mouse skin occurred in a PAR-2- and IL-1-dependent manner. This scenario was duplicated by exogenous IL-1 plus PAR-2-Ag vs. each stimulus alone. Joint activity of PAR-2 and IL-1 was also observed in human keratinocytes. The TSLP promoter was identified as the target of PAR-2/IL-1, whereby PAR-2 activation augmented the recruitment of NF-kappa B and transcriptional activation over IL-1 alone. Combined treatment showed activity at concentrations of IL-1 unable to elicit NF-kappa B activity on their own. Conclusions Skin barrier disruption activates the IL-1 and the PAR-2 pathways, which act in concert to activate the TSLP promoter and possibly other inflammatory genes. Awareness of this combined activity may permit a more flexible clinical management by selective targeting of either pathway individually or collectively.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据