TSLP Down-Regulates S100A7 and ß-Defensin 2 Via the JAK2/STAT3-Dependent Mechanism

Abstract

Elevated T-helper type 2 cytokines in atopic skin, such as IL-4 and IL-13, were thought to be responsible for an impaired expression of antimicrobial proteins, which may contribute to the increased susceptibility to skin infections in patients with atopic dermatitis. In this study, the relationship between thymic stromal lymphopoietin and antimicrobial proteins and the involved molecular pathway was defined in normal human epidermal keratinocytes and human skin equivalent model. Stimulation of normal human epidermal keratinocytes with thymic stromal lymphopoietin decreased both mRNA and levels of S100A7 and human β-defensin 2 in a dose-dependent manner, and the regulation was JAK2/STAT3-dependent. Thymic stromal lymphopoietin decreased the antimicrobial protein expression, even in the presence of IL-17, which is their strong inducer. STAT3 directly regulated the S100A7 and human β-defensin 2 promoters in normal human epidermal keratinocytes. Immunohistochemically, lesional atopic skin stained more intensely with phospho-STAT3 compared with healthy control. Our results show that up-regulated thymic stromal lymphopoietin may contribute to the deficiency of antimicrobial proteins in atopic dermatitis, including S100A7 and human β-defensin 2, by a JAK2/STAT3-dependent mechanism and that STAT3/Sin3a might directly control the transcriptional activity of the antimicrobial protein promoters in normal human epidermal keratinocytes. Taken together, a key role of the JAK2/STAT3/Sin3a signaling pathway in thymic stromal lymphopoietin-mediated immune response in normal human epidermal keratinocytes might give us clues to understanding the pathological signal transductions in atopic dermatitis.

The IL‐13/periostin/IL‐24 pathway causes epidermal barrier dysfunction in allergic skin inflammation

“…Finally, we used the present findings about the IL‐13/periostin/IL‐24 pathway to clarify the underlying mechanism in AD patients. It has been already reported that expression of phosphorylated STAT6 and STAT3 and periostin is enhanced in skins of AD patients correlated with the severity of inflammation . However, no study dealing with IL‐24 expression has been thus far reported.…”

“…It is well known that activation of STAT3 and STAT6 in keratinocytes is enhanced in skin of AD patients . IL‐4 or IL‐13 causes STAT6 activation, whereas several cytokines such as IL‐31, TSLP, and IL‐24, in addition to IL‐4 or IL‐13, activate STAT3 .…”

IL-33 down-regulates CLDN1 expression through the ERK/STAT3 pathway in keratinocytes

“…In addition, STAT3 may be a key regulator of filaggrin expression in human keratinocytes [31]. Our recent study showed that STAT3 was highly expressed in the skin of AD patients [32]. Other reports suggested the involvement of STAT3 in CLDN1 expression [33,34].…”

Arctigenin Attenuates Breast Cancer Progression through Decreasing GM-CSF/TSLP/STAT3/β-Catenin Signaling

“…It has been reported that GM-CSF and TSLP are important players in STAT3 activation [35,36]. And the crosstalk between β-catenin and STAT3 signaling pathways has been reported in breast cancer stem cells [37].…”