title: Proinflammatory properties of murine aortic endothelial cells exclusively expressing a non cleavable form of TNFalpha. Effect on tumor necrosis factor alpha receptor type 2.
abstract: Soluble (sTNF) and transmembrane (tmTNF) forms of TNFalpha (TNF) have distinct proinflammatory effects. We investigated whether tmTNF altered the synthesis of some proinflammatory proteins involved in atherothrombosis, in murine aortas and aortic endothelial cells (MAEC). Samples were obtained from wild-type (WT) mice and TNF-deficient mice that express a mutated non cleavable tmTNF transgene (tmTNFnc). The levels of secreted MCP-1, RANTES, IL-6, PAI-1, soluble ICAM-1, and soluble TNF receptor type 1 (TNFR1; CD120a) antigens, MMP-9 activity and of cell surface ICAM-1 were not significantly different between the two types of MAEC. The magnitude of endotoxin-stimulated production of RANTES, MCP-1 and IL-6 was similar in the two types of cells. Of note, the amount of synthesized TNF receptor type 2 (TNFR2; CD120b), measured by its secreted (in aorta and MAEC), intracellular and mRNA levels (in MAEC), was significantly 4-fold lower in tmTNFnc than in WT mice, both in basal and endotoxin-stimulated conditions. A neutralizing anti-TNF antibody or the recombinant murine TNF did not modify the magnitude of the difference in TNFR2 production between the two types of cells, suggesting a preponderant role of tmTNF in the down-regulation of TNFR2 synthesis. Macrophages of tmTNFnc mice also produced less TNFR2 than WT macrophages (-30%). Plasmas of tmTNFnc mice contained significantly less sTNFR2 than WT mice (-75%). In conclusion, an increase in tmTNF levels, rather than the lack of sTNF, significantly down-modulated TNFR2 synthesis in aortic endothelial cells, but had no major influence on the synthesis of some major pro-inflammatory and pro-atherothrombotic proteins.
authors.affiliation: Inserm UMR-626, Faculté de Médecine, I.P.H.M., 27 Bd. Jean Moulin, 13385 Marseille, Cedex 5, France.
authors.forename: Matthias
authors.initials: M
authors.lastname: Canault
authors.forename: Franck
authors.initials: F
authors.lastname: Peiretti
authors.forename: Christoph
authors.initials: C
authors.lastname: Mueller
authors.forename: Paule
authors.initials: P
authors.lastname: Deprez
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bonardo
authors.forename: Denis
authors.initials: D
authors.lastname: Bernot
authors.forename: Irène
authors.initials: I
authors.lastname: Juhan-Vague
authors.forename: Gilles
authors.initials: G
authors.lastname: Nalbone
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology* / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D003470:Culture Media / Q000494:pharmacology; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013927:Thrombosis / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C515335:Ccr2 protein, mouse; D018946:Chemokine CCL5; D003470:Culture Media; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1