CD147上调成纤维细胞IGFBP-2、5的表达在系统性硬化症患者皮肤纤维化中的作用

Systemic sclerosis(SSc) is an autoimmune disease with multiple organs and systems involved, charaterised histologically with inflammatory cells infiltration in the early stage and tissue fibrosis afterwards. Notably, activation of fibroblasts by inflammatory cells is one of the critical steps of the onset of fibrosis. Insulin-like growth factor-binding protein family(IGFBPs) can be secreted by activated fibroblasts to promote tissue fibrosis. One of the family members, IGFBP-5, is widely accepted to create animal models of skin and pulmonary fibrosis by overexpression in mouse fibroblasts. CD147, which we cloned and persistently worked on, was found highly expressed on activated inflammatory cells and closely related with various autoimmune diseases, and was reported to promote fibrosis. More intriguingly, we detected and proved its ability of upregulating IGFBP2\5 expression in tumor cell lines. Here, we would establish a co-culture system of SSc peripheral skin homing subset of T lymphocytes and lesional fibroblasts to further investigate the role CD147(expressed by skin homing T lymphocytes) plays in upregulating the expression of IGFBP-2\5 in fibroblasts, in activating fibrosis and finally in skin fibrosis. Subsequently, we would use systemical biological and molecular methods to further identify the regulatory mechanism. Based on the above, we would like to provide more evidence for the development of molecular targeted therapy for SSc.

系统性硬化症（SSc）是一类常伴有典型皮肤硬化改变的自身免疫疾病，以早期炎症细胞浸润和后期组织纤维化为特征性病理学表现。炎症细胞作用下成纤维细胞（FLS）的异常活化是纤维化启动的关键。胰岛素样生长因子结合蛋白（IGFBPs）可由活化的FLS分泌，并促进纤维化的发生，其中IGFBP5过表达于小鼠成纤维细胞，已成为建立皮肤和肺纤维化动物模型的公认手段。由本项目组成员克隆、并持续研究的CD147分子在多种自身免疫疾病中高表达于活化的炎症细胞，参与疾病发生，并与组织纤维化关系密切。有趣的是，我们新近发现CD147可显著上调肿瘤细胞IGFBP2\5的表达。本研究将通过SSc患者CD3+CLA+（皮肤特异性）T细胞-FLS共培养体系、干扰T细胞CD147表达等方法，探讨CD147对FLS IGFBP2\5的表达、FLS活化的作用，并明确其作用途径和调控机制，为探索SSc新的发病机制和治疗手段提供依据。