title: CD40-TRAF Signaling Upregulates CX3CL1 and TNF-α in Human Aortic Endothelial Cells but Not in Retinal Endothelial Cells.
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.
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Greene
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Jose-Andres C
authors.initials: JA
authors.lastname: Portillo
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Yalitza
authors.initials: Y
authors.lastname: Lopez Corcino
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.|Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.|Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Subauste
mesh_terms: D001011:Aorta / Q000166:cytology* / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054428:Chemokine CX3CL1 / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D058426:Neointima / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000473:pathology; D012160:Retina / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: C111835:CCL2 protein, human; D019013:CD40 Antigens; C515538:CX3CL1 protein, human; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; C573420:ICAM1 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand