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Grp94与人IgG形成的稳定复合物通过细胞因子样机制促进人脐静脉内皮细胞的血管生成分化。

Stable complexes formed by Grp94 with human IgG promoting angiogenic differentiation of HUVECs by a cytokine-like mechanism.

作者信息

Tramentozzi Elisa, Montopoli Monica, Orso Genny, Pagetta Andrea, Caparrotta Laura, Frasson Martina, Brunati Anna Maria, Finotti Paola

机构信息

Department of Pharmacology and Anesthesiology, University of Padova, L.go E. Meneghetti 2, 35131 Padova, Italy.

出版信息

Mol Immunol. 2008 Aug;45(13):3639-48. doi: 10.1016/j.molimm.2008.04.020. Epub 2008 Jun 12.

Abstract

To explore the molecular mechanisms by which complexes of Grp94 with IgG, purified from the plasma of diabetic subjects, could drive an inflammatory risk in vascular cells, native Grp94 was co-incubated with human, non-immune IgG to obtain the formation of complexes that were then tested on human umbilical vein endothelial cells (HUVECs). Co-incubation of Grp94 with IgG led to the formation of stable, SDS-resistant complexes that displayed effects partly similar and partly significantly different from those of Grp94 alone. Both Grp94 alone and with IgG stimulated the cell growth and promoted angiogenesis by a mechanism of autocrine/paracrine activation of the expression of heat shock protein (HSP)90 and HSP70. However, the most striking alterations in the cell cytoskeleton, characterized by dramatic rearrangement of actin and increased formation of podosomes, were induced by Grp94 with IgG, and were mediated by the enhanced expression of HSP90. At variance with Grp94 alone, Grp94 with IgG promoted the angiogenic differentiation by activating a signaling pathway apparently independent of the intense stimulation of the ERK1/2 pathway that was instead more directly involved in mediating the proliferative effects on HUVECs. Results show unprecedented cytokine-like effects of Grp94 and a so far undisclosed capacity to bind irreversibly IgG, forming complexes that, with respect to Grp94 alone, display a more intense angiogenic transforming capacity that may predict an increased inflammatory risk in vascular cells in vivo.

摘要

为了探究从糖尿病患者血浆中纯化得到的Grp94与IgG的复合物驱动血管细胞炎症风险的分子机制,将天然Grp94与人源非免疫IgG共同孵育,以形成复合物,然后在人脐静脉内皮细胞(HUVECs)上进行测试。Grp94与IgG共同孵育导致形成稳定的、耐SDS的复合物,其表现出的效应部分与单独的Grp94相似,部分则显著不同。单独的Grp94以及与IgG共同存在时,均通过热休克蛋白(HSP)90和HSP70表达的自分泌/旁分泌激活机制刺激细胞生长并促进血管生成。然而,Grp94与IgG诱导了细胞细胞骨架最显著的改变,其特征为肌动蛋白的剧烈重排和足体形成增加,这是由HSP90表达增强介导的。与单独的Grp94不同,Grp94与IgG通过激活一条明显独立于ERK1/2途径强烈刺激的信号通路来促进血管生成分化,而ERK1/2途径更直接参与介导对HUVECs的增殖作用。结果显示Grp94具有前所未有的细胞因子样效应,以及迄今未被揭示的不可逆结合IgG的能力,形成的复合物相对于单独的Grp94具有更强的血管生成转化能力,这可能预示着体内血管细胞炎症风险增加。

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