A CD40-CD154 Interaction in Tissue Fibrosis
A CD40-CD154 Interaction in Tissue Fibrosis
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DOI：
10.1002/art.23994
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发表时间：
2008-11-01
影响因子：
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通讯作者：
Kuwana, Masataka
中科院分区：
文献类型：
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作者：
Kawai, Masataka;Masuda, Ayako;Kuwana, Masataka
客观的。通过 CD40-CD154 参与来检查成纤维细胞和单核浸润之间的相互作用在组织纤维化发展中的作用。方法。通过腺病毒基因转移诱导源自健康皮肤的培养真皮成纤维细胞表达 CD40，用可溶性 CD154 刺激，并在体外评估增殖、基因表达和蛋白质表达。评估博莱霉素诱导的皮肤硬化小鼠皮肤（系统性硬化症 (SSc) 模型）的 CD40 和 CD154 表达、体内成纤维细胞增殖以及特定基因的表达。还检查了抗 CD154 单克隆抗体对博来霉素诱导的皮肤硬化的影响。结果。在可溶性 CD154 刺激下，通过腺病毒基因转移诱导表达 CD40 的培养成纤维细胞增殖，并表现出细胞间粘附分子 1、白细胞介素 6 (IL-6)、IL-8、单核细胞趋化蛋白 1 (MCP-1) 和 RANTES 基因及其蛋白质的上调。在博来霉素处理的小鼠皮肤中，真皮成纤维细胞表达 CD40，肥大细胞和 CD4+ T 细胞表达 CD154。电子显微镜分析显示成纤维细胞以原始接触方式附着在肥大细胞和 T 细胞上。成纤维细胞的增殖和MCP-1基因表达的上调先于真皮增厚。最后，抗CD154抗体通过抑制成纤维细胞增殖和下调MCP-1表达来抑制博来霉素诱导的皮肤硬化。结论。成纤维细胞与肥大细胞或 T 细胞之间通过 CD40-CD154 信号传导的相互作用对于纤维化过程早期成纤维细胞的激活至关重要。阻断 CD40-CD154 信号可能是治疗人类纤维化疾病（如 SSc）的一种新策略。
Objective. To examine the role of an interaction between fibroblasts and mononuclear infiltrates through CD40-CD154 engagement in the development of tissue fibrosis.Methods. Cultured dermal fibroblasts derived from healthy skin were induced to express CD40 by adenoviral gene transfer, stimulated with soluble CD154, and evaluated for proliferation, gene expression, and protein expression in vitro. The skin of mice with bleomycin-induced skin sclerosis, a model for systemic sclerosis (SSc), was assessed for CD40 and CD154 expression, in vivo fibroblast proliferation, and the expression of specific genes. The effects of an anti-CD154 monoclonal antibody on bleomycin-induced skin sclerosis were also examined.Results. Upon stimulation with soluble CD154, cultured fibroblasts induced to express CD40 by adenoviral gene transfer proliferated and showed up-regulation of the genes for intercellular adhesion molecule 1, interleukin-6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1), and RANTES, as well as up-regulation of their proteins. In the skin from bleomycin-treated mice, dermal fibroblasts expressed CD40, and mast cells and CD4+ T cells expressed CD154. Electron microscopic analysis revealed fibroblasts attached to mast cells and T cells with primitive contacts. The proliferation of fibroblasts and the up-regulated MCP-1 gene expression preceded thickening of the dermis. Finally, the anti-CD154 antibody inhibited the bleomycin-induced skin sclerosis by suppressing fibroblast proliferation and down-regulating MCP-1 expression.Conclusion. The interaction between fibroblasts and mast cells or T cells through CD40-CD154 signaling is critical for fibroblast activation early in the course of fibrosis. Blockade of the CD40-CD154 signal may be a novel therapeutic strategy for human fibrotic diseases, such as SSc.