Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
J Allergy Clin Immunol. 2010 Nov;126(5):985-93, 993.e1-3. doi: 10.1016/j.jaci.2010.09.002.
Staphylococcus aureus heavily colonizes the lesions of patients with atopic dermatitis (AD) and is known to trigger a worsening of AD. However, the exact mechanism by which S. aureus promotes AD is unknown. Thymic stromal lymphopoietin (TSLP), which is highly expressed by keratinocytes in skin lesions of patients with AD and bronchial epithelial cells in asthmatic patients, represents a critical factor linking responses at interfaces between the body and the environment to allergic type 2 immune responses.
We sought to examine the ability of synthetic lipopeptides and S. aureus to induce TSLP expression in human keratinocytes and identify the pathway of induction.
We stimulated primary human keratinocytes with lipopeptides and S. aureus-derived materials. The release and gene expression of TSLP were measured by means of ELISA and quantitative PCR, respectively.
Diacylated lipopeptide upregulated the expression of TSLP and other proinflammatory molecules. Heat-killed S. aureus and the subcellular fractions of S. aureus induced TSLP's release, with the membranous fraction having the greatest activity. Small interfering RNA-mediated knockdown of either Toll-like receptor (TLR) 2 or TLR6 inhibited the diacylated lipopeptide- and S. aureus membrane-induced TSLP gene expression. S. aureus membrane- and diacylated lipopeptide-induced release of TSLP was enhanced by T(H)2/TNF-α cytokines and partially suppressed by IFN-γ and TGF-β.
The results suggest that ligands for the TLR2-TLR6 heterodimer in S. aureus membranes, including diacylated lipoproteins, could promote T(H)2-type inflammation through TSLP production in keratinocytes, providing an overall picture of the vicious cycles between colonization by S. aureus and AD in the T(H)2-skewed sensitization process, exacerbation of the disease, or both.
金黄色葡萄球菌大量定植于特应性皮炎（AD）患者的皮损中，已知其可诱发 AD 恶化。然而，金黄色葡萄球菌促进 AD 的确切机制尚不清楚。胸腺基质淋巴细胞生成素（TSLP）在 AD 患者皮损中的角质形成细胞和哮喘患者的支气管上皮细胞中高度表达，是将机体与环境之间的反应与过敏性 2 型免疫反应联系起来的关键因素。
我们试图研究合成脂肽和金黄色葡萄球菌诱导人角质形成细胞表达 TSLP 的能力，并确定诱导途径。
我们用脂肽和金黄色葡萄球菌衍生的物质刺激原代人角质形成细胞。通过 ELISA 和定量 PCR 分别测量 TSLP 的释放和基因表达。
双酰化脂肽上调了 TSLP 和其他促炎分子的表达。热灭活金黄色葡萄球菌和金黄色葡萄球菌的亚细胞成分诱导 TSLP 的释放，其中膜部分具有最大的活性。Toll 样受体（TLR）2 或 TLR6 的小干扰 RNA 介导的敲低抑制了双酰化脂肽和金黄色葡萄球菌膜诱导的 TSLP 基因表达。金黄色葡萄球菌膜和双酰化脂肽诱导的 TSLP 释放被 T(H)2/TNF-α 细胞因子增强，部分被 IFN-γ 和 TGF-β 抑制。
这些结果表明，金黄色葡萄球菌膜中 TLR2-TLR6 异二聚体的配体，包括双酰化脂蛋白，可通过角质形成细胞中 TSLP 的产生促进 T(H)2 型炎症，为金黄色葡萄球菌定植与 AD 之间在 T(H)2 偏向性致敏过程中、疾病恶化或两者兼有的恶性循环提供了全面的认识。
