Laboratory of Veterinary Molecular Pathology and Therapeutics, Division of Animal Life Science, Graduate School, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.
J Allergy Clin Immunol. 2011 Feb;127(2):420-429.e1-6. doi: 10.1016/j.jaci.2010.10.043. Epub 2011 Jan 5.
Dendritic cells (DCs) are one of the key regulators for the initiation of allergic responses in patients with atopic dermatitis (AD), being strongly triggered by epithelial cell-derived thymic stromal lymphopoietin (TSLP). Because peroxisome proliferator-activated receptor (PPAR) γ acts as a negative regulator in immune cells, suppressive properties of PPARγ in allergic responses have been proposed.
Because pieces of evidence must be organized to identify the exact role of PPARγ in immune regulation, we explored the suppressive effects of a PPARγ agonist on various functions of DCs and the onset of AD in a murine model.
Effects of rosiglitazone (RSG) on DCs that were derived from NC/Tnd mice, a model for human AD, were analyzed. RSG was administered to NC/Tnd mice to evaluate its preventive and therapeutic effects on the development of AD.
RSG inhibited TSLP-induced DC maturation through downregulation of costimulatory molecules. TSLP-promoted expressions of chemokines in DCs were also suppressed by RSG treatment. Moreover, we showed the necessity of matrix metalloproteinase 9 in TSLP-promoted DC migration by using DCs derived from matrix metalloproteinase 9-deficient NC/Tnd mice, as well as the suppressive effect of PPARγ in the process. Daily oral administration of RSG to NC/Tnd mice before the onset of AD revealed a significant reduction in severity of skin lesions and scratching behavior. In mice treated with RSG, both expression of TSLP in the skin and maturation and migration of DCs were markedly suppressed.
PPARγ can be provided as an inhibitory regulator of TSLP-stimulated DCs in the onset of allergic reactions.
树突状细胞（DCs）是特应性皮炎（AD）患者过敏反应起始的关键调节者之一，强烈受上皮细胞衍生的胸腺基质淋巴细胞生成素（TSLP）触发。由于过氧化物酶体增殖物激活受体（PPAR）γ在免疫细胞中起负调节作用，因此提出了 PPARγ 在过敏反应中的抑制作用。
由于必须组织证据以确定 PPARγ 在免疫调节中的确切作用，我们在小鼠模型中探索了 PPARγ 激动剂对 DC 各种功能和 AD 发病的抑制作用。
分析了来自 NC/Tnd 小鼠（人类 AD 模型）的 DC 中罗格列酮（RSG）的作用。给予 NC/Tnd 小鼠 RSG 以评估其对 AD 发展的预防和治疗作用。
RSG 通过下调共刺激分子抑制 TSLP 诱导的 DC 成熟。RSG 处理还抑制了 TSLP 促进的 DC 中趋化因子的表达。此外，我们通过使用来自基质金属蛋白酶 9 缺陷型 NC/Tnd 小鼠的 DC 展示了 TSLP 促进的 DC 迁移中基质金属蛋白酶 9 的必要性，以及 PPARγ 在该过程中的抑制作用。在 AD 发病前对 NC/Tnd 小鼠进行每日口服 RSG 治疗，可显著减轻皮肤损伤和搔抓行为的严重程度。在接受 RSG 治疗的小鼠中，皮肤中 TSLP 的表达以及 DC 的成熟和迁移均明显受到抑制。
PPARγ 可作为过敏反应中 TSLP 刺激的 DC 的抑制调节因子。
