A critical role for TNFalpha 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 (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.
Mateo
Teresa
T
Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain.
Naim Abu Nabah
Yafa
Y
Losada
Mercedes
M
Estellés
Rossana
R
Company
Chantal
C
Bedrina
Begoña
B
Cerdá-Nicolás
Jose Miguel
JM
Poole
Stephen
S
Jose
Peter J
PJ
Cortijo
Julio
J
Morcillo
Esteban J
EJ
Sanz
Maria-Jesus
MJ
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
D018925:Chemokines; C508598:IL4 protein, human; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D015847:Interleukin-4