title: A critical role for TNFalpha in the selective attachment of mononuclear leukocytes to angiotensin-II-stimulated arterioles.
abstract: 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 (TNFalpha) in the leukocyte accumulation elicited by Ang-II. Ang-II (1 nM intraperitoneally in rats) induced TNFalpha release at 1 hour followed by neutrophil and mononuclear cell recruitment. The administration of an antirat TNFalpha antiserum had no effect on Ang-IIinduced neutrophil accumulation but inhibited the infiltration of mononuclear cells and reduced CC chemokine content in the peritoneal exudate. Pretreatment with either an anti-TNFalpha 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 TNFalpha was found in the postcapillary venules of Ang-II-injected animals, this cytokine was clearly up-regulated in the arterioles. Stimulation of human umbilical arterial endothelial cells (HUAECs) or isolated human mononuclear cells with 1 microM Ang-II caused increased TNFalpha mRNA expression and protein. Neutralization of TNFalpha activity reduced Ang-II-induced MCP-1, MCP-3, and RANTES release from HUAECs and MIP-1alpha from blood cells. In conclusion, the selective mononuclear leukocyte adhesion to Ang-II-stimulated arterioles is largely mediated by TNFalpha in cooperation with constitutive IL-4. Therefore, neutralization of TNFalpha activity may help to prevent mononuclear cell infiltration and the progression of the atherogenic process.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Mateo
authors.forename: Yafa
authors.initials: Y
authors.lastname: Naim Abu Nabah
authors.forename: Mercedes
authors.initials: M
authors.lastname: Losada
authors.forename: Rossana
authors.initials: R
authors.lastname: Estellés
authors.forename: Chantal
authors.initials: C
authors.lastname: Company
authors.forename: Begoña
authors.initials: B
authors.lastname: Bedrina
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Cerdá-Nicolás
authors.forename: Stephen
authors.initials: S
authors.lastname: Poole
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Jose
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Morcillo
authors.forename: Maria-Jesus
authors.initials: MJ
authors.lastname: Sanz
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001160:Arterioles / Q000378:metabolism*; D002448:Cell Adhesion; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000378:metabolism
chemical_list: D018925:Chemokines; C508598:IL4 protein, human; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D015847:Interleukin-4