Proinflammatory properties of murine aortic endothelial cells exclusively expressing a non cleavable form of TNFα

Matthias Canault; Franck Peiretti; Christoph Mueller; Paule Deprez; Bernadette Bonardo; Denis Bernot; Irène Juhan-Vague; Gilles Nalbone

doi:10.1160/TH04-06-0344

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(06): 1428-1437
DOI: 10.1160/TH04-06-0344

Endothelium and Vascular Development

Schattauer GmbH

Proinflammatory properties of murine aortic endothelial cells exclusively expressing a non cleavable form of TNFα

Effect on tumor necrosis factor α receptor type 2

Matthias Canault

²Inserm UMR-626, Faculté de Médecine, I.P.H.M., Marseille, France

,

Franck Peiretti

²Inserm UMR-626, Faculté de Médecine, I.P.H.M., Marseille, France

,

Christoph Mueller

¹Division of Immunopathology, Institute of Pathology, Bern, Switzerland

,

Paule Deprez

²Inserm UMR-626, Faculté de Médecine, I.P.H.M., Marseille, France

,

Bernadette Bonardo

²Inserm UMR-626, Faculté de Médecine, I.P.H.M., Marseille, France

,

Denis Bernot

²Inserm UMR-626, Faculté de Médecine, I.P.H.M., Marseille, France

,

Irène Juhan-Vague

²Inserm UMR-626, Faculté de Médecine, I.P.H.M., Marseille, France

,

Gilles Nalbone

²Inserm UMR-626, Faculté de Médecine, I.P.H.M., Marseille, France

› Author Affiliations

Abstract

Summary

Soluble (sTNF) and transmembrane (tmTNF) forms of TNFα (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.

Keywords

Transmembrane TNFα - TNFR2/CD120b - aortic endothelial cells - cytokines - chemokines

Full Text

References

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