Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation
Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation
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DOI：
10.1038/jid.2008.74
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发表时间：
2008-09-01
影响因子：
6.5
通讯作者：
Leung, Donald Y. M.
中科院分区：
文献类型：
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作者：
Howell, Michael D.;Fairchild, Heather R.;Leung, Donald Y. M.
特应性皮炎（AD）是一种与频繁皮肤感染和皮肤屏障功能受损相关的炎症性皮肤病。最近的研究表明，增加Th 2细胞因子的表达有助于减少抗菌肽和减少丝聚蛋白（FLG）的表达，然而，导致这种效果的机制是未知的。使用蛋白质组学，我们发现S100钙结合蛋白All（SlOO/All）在IL-4和IL-13的存在下显著下调。培养角质形成细胞的钙浓度增加显着诱导S100/A11的表达。这与人β-防御素（HBD）-3和FLG表达的增加相对应。通过siRNA干扰S-100/A11的表达，抑制HBD-3和FLG的诱导。此外，钙离子介导的HBD-3和FLG诱导需要S100/All下游的细胞周期蛋白依赖性激酶抑制剂p21。重要的是，p21重组蛋白转导到角质形成细胞阻止IL-4/IL-13介导的FLG和HBD-3表达的抑制。S100/A11和p21基因表达在急性和慢性AD皮肤中也被发现显著降低。这项研究证明了S-100/A11和p21在调节皮肤屏障完整性和先天免疫应答中的重要作用。
Atopic dermatitis (AD) is an inflammatory skin disease associated with frequent skin infection and impaired skin barrier function. Recent studies indicate that increased Th2 cytokine expression contributes to reduction in antimicrobial peptides and reduced filaggrin (FLG) expression, however, the mechanisms leading to this effect is unknown. Using proteomics, we found the S100 calcium-binding protein All (SlOO/All) to be significantly downregulated in the presence of IL-4 and IL-13. Culturing keratinocytes with increased calcium concentrations significantly induced S100/A11 expression. This corresponded with an increase in human beta-defensin (HBD)-3 and FLG expression. Interference of S-100/A11 expression, by siRNA, inhibited induction of HBD-3 and FLG. Furthermore p21, a cyclin-dependent kinase inhibitor downstream of S100/All, was required for calcium-mediated induction of HBD-3 and FLG. Importantly, transduction of p21-recombinant protein into keratinocytes prevented IL-4/IL-13-mediated inhibition of FLG and HBD-3 expression. S100/A11 and p21 gene expression was also found to be significantly lower in acute and chronic AD skin. This study demonstrates an important role for S-100/A11 and p21 in regulating skin barrier integrity and the innate immune response.