【作者】 裴新辉；

【导师】 林志新； 耿建国；

【作者基本信息】 上海交通大学 ， 生物化学与分子生物学， 2008， 博士

【摘要】 血清淀粉样P蛋白(SAP)、C-反应蛋白(CRP)隶属于正五聚体蛋白家族(pentraxins)。SAP与CRP为肝脏表达的血清蛋白,它们在急性炎症反应中会急剧上调表达。在临床检测中,可以通过检测其表达水平来反映患者炎症水平,但是其在炎症中的确切功能却是未知的。选凝素家族蛋白(CD62)包括P-选凝素(P-selectin)、E-选凝素(E-selectin)和L-选凝素(L-selectin)等三种蛋白,它们是种单次跨膜糖蛋白。它们是炎症或者机体免疫过程中白细胞迁移的关键性粘附分子,但是目前人们并不知道究竟是什么在负调控选凝素的功能。我们发现SAP、CRP可以与选凝素家族蛋白相互作用,同时发现它们可以抑制选凝素结合到HL-60(人多形核细胞株)上,而且鼠SAP还可以抑制白细胞在鼠微静脉上的滚动。更重要的是,在几种小鼠的炎症模型中,比如说:急性腹膜炎、急性胸膜炎、急性肺炎以及卵清蛋白(OVA)诱导的哮喘等模型中,SAP和CRP可以抑制白细胞(包括;中性粒细胞、嗜酸性粒细胞等)向炎症部位的迁移。而且在SAP转基因小鼠中,白细胞的迁移也会减弱,但是在SAP基因敲除小鼠中白细胞的迁移却是增强的。我们的发现证明,炎症反应蛋白(SAP、CRP)是选凝素家族蛋白的内在性负反馈调控因子,它们可以调节炎症过程中白细胞向炎症部位迁移的规模。更多还原

【Abstract】 Serum amyloid P component (SAP) and C-reactive protein (CRP) are two classic short pentraxins secreted by hepatocytes in response to inflammatory challenges. Although widely used as a clinical indicator for inflammation, the functional role of circulating acute-phase proteins remains poorly understood in acute inflammation. The selectin (CD62) family of cell adhesion molecules mediates leukocyte trafficking and plays essential roles in leukocyte recruitment in host defense and innate immunity. However, the feedback mechanism for negative regulation of selectin-mediated leukocyte adhesion is currently not well understood.Here we report that SAP and CRP bound to P-, E- and L-selectins (CD62P, E and L), inhibiting selectin binding to human promyeloid HL-60 cells and neutralizing leukocyte rolling on activated capillary venules. Importantly, SAP and CRP potently suppressed infiltration and deposition of leukocytes, such as neutrophils and eosinophils, in several murine inflammatory models including allergic lung inflammation induced by ovalbumin (OVA) sensitization. Consistent with this result, leukocyte accumulation was significantly reduced in SAP transgenic mice, but dramatically exaggerated in SAP-deficient (SAP-/-) mice.Our findings thus demonstrate that acute-phase proteins, such as SAP and CRP, act as endogenous inhibitors of all three selectins for negative modulation of leukocyte trafficking during inflammation.更多还原