A critical role for TNFα in the selective attachment of mononuclear leukocytes to angiotensin-II-stimulated arterioles

Angiotensin II (Ang-II) exerts inflammatory activity and is involved in different cardiovascular disorders. This study has evaluated the involvement of tumor necrosis factor alpha (TNF alpha) in the leukocyte accumulation elicited by Ang-II. Ang-II (1 nM intraperitoneally in rats) induced TNFa release at 1 hour followed by neutrophil and mononuclear cell recruitment. The administration of an antirat TNFa antiserum had no effect on Ang-II-induced neutrophil accumulation but inhibited the infiltration of mononuclear cells and reduced CC chemokine content in the peritoneal exudate. Pretreatment with either an anti-TNF alpha or an anti-IL-4 antiserum decreased Ang-II-induced arteriolar mononuclear leukocyte adhesion by 68% and 60%, respectively, in the rat mesenteric microcirculation. While no expression of TNFa was found in the postcapillary venules of Ang-II-injected animals, this cytokine was clearly upregulated in the arterioles. Stimulation of human umbilical arterial endothelial cells (HUAECs) or isolated human mononuclear cells with 1 mu M Ang-II caused increased TNFa mRNA expression and protein. Neutralization of TNFa activity reduced Ang-II-induced MCP-1, MCP-3, and RANTES release from HUAECs and MIP-1 alpha from blood cells. In conclusion, the selective mononuclear leukocyte adhesion to Ang-II-stimulated arterioles is largely mediated by TNFa in cooperation with constitutive IL-4. Therefore, neutralization of TNFa activity may help to prevent mononuclear cell infiltration and the progression of the atherogenic process.