A CRITICAL ROLE FOR TNFα IN THE SELECTIVE ATTACHMENT OF MONONUCLEAR LEUKOCYTES TO ANGIOTENSIN-II-STIMULATED ARTERIOLES Short title: TNFα involvement on Ang-II arteriolar adhesion

Angiotensin II (Ang-II) exerts inflammatory activity and is involved in different cardiovascular disorders. This study has evaluated the involvement of TNFα in the leukocyte accumulation elicited by Ang-II. Ang-II (1 nmol/L, i.p., in rats) induced TNFα release at 1h followed by neutrophil and mononuclear cell recruitment. The administration of an anti-rat TNFα 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-TNFα 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 TNFα was found in the post-capillary venules of Ang-II injected animals, this cytokine was clearly up-regulated in the arterioles. Stimulation of HUAECs or isolated human mononuclear cells with 1 μmol/L Ang-II caused increased TNFα mRNA expression and protein. Neutralization of TNFα activity reduced Ang-II-induced MCP-1, MCP-3 and RANTES release from HUAECs and MIP-1α from blood cells. In conclusion, the selective mononuclear leukocyte adhesion to Ang-II stimulated arterioles is largely mediated by TNFα in cooperation with constitutive IL-4. Therefore, neutralization of TNFα activity may help to prevent mononuclear cell infiltration and the progression of the atherogenic process. only. For personal use at PENN STATE UNIVERSITY on February 21, 2013. bloodjournal.hematologylibrary.org From