Tachibana M, Wada K, Katayama K, Kamisaki Y, Maeyama K, Kadowaki T, Blumberg R S, Nakajima A
Gastroenterology Division, Yokohama City University School of Medicine, Yokohama, Japan.
Allergy. 2008 Sep;63(9):1136-47. doi: 10.1111/j.1398-9995.2008.01677.x. Epub 2008 Jun 10.
Mast cells play a central role in allergic and inflammatory diseases. Several reports indicated role of peroxisome proliferator-activated receptor gamma (PPARgamma) on mast cell function. However, there is no report about the role of PPARgamma on differentiation of mast cells from the progenitors. In this study, we investigated the role of PPARgamma in regulating bone marrow-derived mast cell maturation and the therapeutic implications for mast cell-related diseases such as atopic or contact dermatitis.
We used in vitro cell culture system for mast cell differentiation from bone marrow-progenitors using specific ligands and lentiviral-mediated short hairpin RNA of PPARgamma, and in vivo murine dermatitis models.
Activation of PPARgamma inhibited the maturation of bone marrow progenitors into connective tissue-type mast cells (CTMCs) through up-regulation of GATA-4 and GATA-6 resulting in a decrease in expression of histidine decarboxylase and mast cell histamine content. In comparison, the differentiation of bone marrow progenitors into CTMCs was significantly accelerated by the knockdown of PPARgamma expression by lentiviral-mediated short hairpin RNA. Peroxisome proliferator-activated receptor gamma ligand administration to mice inhibited the maturation of mast cells resulting in attenuation of atopic and contact dermatitis via diminishment of the number of mature mast cells.
Our results indicate that PPARgamma is one of master regulators on mast cell maturation and potentially useful for the therapy in various disorders involving mast cell activation.
肥大细胞在过敏性和炎性疾病中起核心作用。多项报告指出过氧化物酶体增殖物激活受体γ（PPARγ）在肥大细胞功能方面的作用。然而，尚无关于PPARγ在祖细胞来源的肥大细胞分化中作用的报告。在本研究中，我们调查了PPARγ在调节骨髓来源的肥大细胞成熟中的作用以及对肥大细胞相关疾病如特应性皮炎或接触性皮炎的治疗意义。
我们使用体外细胞培养系统，利用特定配体和PPARγ的慢病毒介导短发夹RNA从骨髓祖细胞诱导肥大细胞分化，并建立体内小鼠皮炎模型。
PPARγ的激活通过上调GATA-4和GATA-6抑制骨髓祖细胞向结缔组织型肥大细胞（CTMCs）的成熟，导致组氨酸脱羧酶表达和肥大细胞组胺含量降低。相比之下，慢病毒介导的短发夹RNA敲低PPARγ表达可显著加速骨髓祖细胞向CTMCs的分化。给小鼠施用过氧化物酶体增殖物激活受体γ配体可抑制肥大细胞成熟，通过减少成熟肥大细胞数量减轻特应性皮炎和接触性皮炎。
我们的结果表明PPARγ是肥大细胞成熟的主要调节因子之一，对涉及肥大细胞激活的各种疾病的治疗可能有用。
