Abstract
CD40, CX3CL1 and TNF-α promote atheroma and neointima formation. CD40 and TNF-α are also central to the development of diabetic retinopathy while CX3CL1 may play a role in the pathogenesis of this retinopathy. The purpose of this study was to examine whether CD40 ligation increases CX3CL1 and TNF-α protein expression in human endothelial cells from the aorta and retina. CD154 (CD40 ligand) upregulated membrane-bound and soluble CX3CL1 in human aortic endothelial cells. CD154 triggered TNF-α production by human aortic endothelial cells. TNF Receptor Associated Factors (TRAF) are key mediators of CD40 signaling. Compared to human aortic endothelial cells that express wt CD40, cells that express CD40 with a mutation that prevents TRAF2,3 recruitment, or CD40 with a mutation that prevents TRAF6 recruitment exhibited a profound inhibition of CD154-driven upregulation of membrane bound and soluble CX3CL1 as well as of TNF-α secretion. While both CD154 and TNF-α upregulated CX3CL1 in human aortic endothelial cells, these stimuli could act independently of each other. In contrast to human aortic endothelial cells, human retinal endothelial cells did not increase membrane bound or soluble CX3CL1 expression or secrete TNF-α in response to CD154 even though CD40 ligation upregulated ICAM-1 and CCL2 in these cells. Moreover, TNF-α did not upregulate CX3CL1 in retinal endothelial cells. In conclusion, CD40 ligation increases CX3CL1 protein levels and induces TNF-α production in endothelial cells. However, endothelial cells are heterogeneous in regards to these responses. Human aortic but not retinal endothelial cells upregulated CX3CL1 and TNF-α in response to CD40 ligation, as well as upregulated CX3CL1 in response to TNF-α. These dissimilarities may contribute to differences in regulation of inflammation in large vessels versus the retina.
Highlights
Activated endothelial cells express various adhesion molecules and secrete chemokines that promote leukocyte recruitment and foster inflammation [1]
We focused on human aortic endothelial cells (HAEC) and human retinal endothelial cells (HREC) to determine whether these responses may be affected by the tissue of origin of endothelial cells
We examined whether CD40 ligation upregulates membrane bound CX3CL1 on HAEC
Summary
Activated endothelial cells express various adhesion molecules and secrete chemokines that promote leukocyte recruitment and foster inflammation [1]. Endothelial cell activation occurs in disorders with an inflammatory component including atherosclerosis and microvascular complications of diabetes [2,3]. CX3CL1 (fractalkine) is a chemokine that exists in a membrane-bound and a soluble form [4]. CX3CL1 is synthesized as a membrane-bound chemokine with a transmembrane domain and a chemokine domain positioned on top of a mucin-like stalk [4]. In this form, CX3CL1 promotes adhesion of monocytes, T cells and NK cells [5,6]. The two forms of this molecule explain why CX3CL1 can have both adhesion molecule and chemokine functions
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