Yamamoto Toshiyuki, Nishioka Kiyoshi
Department of Dermatology, Tokyo Medical and Dental University School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
J Invest Dermatol. 2003 Sep;121(3):510-6. doi: 10.1046/j.1523-1747.2003.12408.x.
Systemic sclerosis is a connective tissue disease characterized by excessive deposition of extracellular matrix in the skin as well as various internal organs. Cellular infiltrates are found in the dermis in early systemic sclerosis, which are suggested to play an important part. Recent studies suggest the involvement of monocyte chemoattractant protein-1, a C-C chemokine, in the fibrotic process. This study examines the role of monocyte chemoattractant protein-1 in the induction of dermal sclerosis in a murine model of bleomycin-induced scleroderma. Immunohistochemical analysis showed that expression of monocyte chemoattractant protein-1 in the infiltrating mononuclear cells was enhanced at 2 to 3 wk following bleomycin treatment, whereas expression of monocyte chemoattractant protein-1 in fibroblasts was detected at later stages in the sclerotic skin. Reverse transcriptase-polymerase chain reaction analysis showed that monocyte chemoattractant protein-1 mRNA expression in the lesional skin peaked at 2 to 3 wk following bleomycin treatment. Expression of CCR-2, a major receptor for monocyte chemo-attractant protein-1, was also upregulated in the lesional skin at both protein and mRNA levels following bleomycin treatment. Administration of anti-monocyte chemoattractant protein-1 neutralizing antibody together with local bleomycin treatment reduced dermal sclerosis, along with a decrease of collagen content in the skin as well as mRNA expression of type I collagen. In vitro analysis showed that stimulation with monocyte chemoattractant protein-1 (10 ng per mL) upregulated alpha1(I) collagen and decorin mRNA expression in normal dermal fibroblasts, whereas mRNA levels of fibronectin and biglycan were not altered. These data suggest that monocyte chemoattractant protein-1 and CCR-2 signaling plays an important part in the pathogenesis of bleomycin-induced scleroderma. Monocyte chemoattractant protein-1 may contribute to the induction of dermal sclerosis via its direct effect of upregulation of mRNA expression of extracellular matrix on fibroblasts, as well as indirect effect mediated by a number of cytokines released from immunocytes recruited into the lesional skin.
系统性硬化症是一种结缔组织疾病，其特征是皮肤以及各种内脏器官中细胞外基质过度沉积。在早期系统性硬化症的真皮中可发现细胞浸润，提示其发挥重要作用。最近的研究表明，单核细胞趋化蛋白-1（一种C-C趋化因子）参与了纤维化过程。本研究在博来霉素诱导的硬皮病小鼠模型中，检测单核细胞趋化蛋白-1在诱导真皮硬化中的作用。免疫组化分析显示，博来霉素治疗后2至3周，浸润的单核细胞中单核细胞趋化蛋白-1的表达增强，而在硬化皮肤的后期阶段可检测到成纤维细胞中单核细胞趋化蛋白-1的表达。逆转录聚合酶链反应分析显示，博来霉素治疗后2至3周，病变皮肤中单核细胞趋化蛋白-1 mRNA表达达到峰值。博来霉素治疗后，单核细胞趋化蛋白-1的主要受体CCR-2在病变皮肤中的蛋白和mRNA水平也上调。局部注射博来霉素时给予抗单核细胞趋化蛋白-1中和抗体可减轻真皮硬化，同时皮肤中胶原蛋白含量以及I型胶原蛋白mRNA表达均降低。体外分析表明，用单核细胞趋化蛋白-1（10 ng/mL）刺激可上调正常真皮成纤维细胞中α1（I）胶原蛋白和核心蛋白聚糖mRNA表达，而纤连蛋白和双糖链蛋白聚糖的mRNA水平未改变。这些数据表明，单核细胞趋化蛋白-1和CCR-2信号通路在博来霉素诱导的硬皮病发病机制中起重要作用。单核细胞趋化蛋白-1可能通过直接上调成纤维细胞中细胞外基质mRNA表达以及由募集到病变皮肤中的免疫细胞释放的多种细胞因子介导的间接作用，促进真皮硬化的诱导。
