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Jose-Andres C. Portillo, Jennifer A. Greene, Ram H. Nagaraj, Carlos Subauste; Advanced Glycation End Products Upregulate CD40 in Endothelial Cells and Muller Cells and Promote CD40-dependent Pro-inflammatory Responses. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2430.
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Advanced glycation end products (AGEs) play an important role in the pathogenesis of vascular complications of diabetes. These disorders have an important inflammatory component. CD40 is a member of the TNF receptor superfamily that promotes various pro-inflammatory responses. We examined the effects of AGEs on CD40 expression on endothelial cells and Muller cells as well as on CD40-mediated pro-inflammatory responses.
Human primary endothelial cells and Muller cells were incubated with methyl glyoxal (MGO)-modified fibronectin, MGO-modified human serum albumin or appropriate controls. CD40 expression was assessed by flow cytometry. Control or AGE-treated cells were incubated with or without CD154 (CD40 ligand). Expression of ICAM-1 and MCP-1 were examined by flow cytometry or ELISA respectively.
Incubation with MGO induced expression of AGEs in fibronectin as assessed by immunofluorescence using anti-antibodies against hydroimidazolone or argpyrimidine. MGO-modified fibronectin as well as MGO-modified human serum albumin upregulated CD40 on primary human retinal endothelial cells, aortic endothelial cells and Muller cells. CD40 upregulation was of functional relevance. Compared to endothelial cells incubated with control fibronectin, endothelial cells incubated with MGO-modified fibronectin exhibited higher upregulation of ICAM-1 and MCP-1 production in response to CD154. Similarly, Muller cells incubated with MGO-modified fibronectin produced higher amounts of MCP-1 and expressed higher levels of ICAM-1 after CD154 stimulation.
These studies revealed that AGEs are modulators of CD40 expression in endothelial cells and Muller cells and enhance CD40-dependent pro-inflammatory responses.
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