title: Regulation of T-cell function by endogenously produced angiotensin II.
abstract: The adaptive immune response and, in particular, T cells have been shown to be important in the genesis of hypertension. In the present study, we sought to determine how the interplay between ANG II, NADPH oxidase, and reactive oxygen species modulates T cell activation and ultimately causes hypertension. We determined that T cells express angiotensinogen, the angiotensin I-converting enzyme, and renin and produce physiological levels of ANG II. AT1 receptors were primarily expressed intracellularly, and endogenously produced ANG II increased T-cell activation, expression of tissue homing markers, and production of the cytokine TNF-alpha. Inhibition of T-cell ACE reduced TNF-alpha production, indicating endogenously produced ANG II has a regulatory role in this process. Studies with specific antagonists and T cells from AT1R and AT2R-deficient mice indicated that both receptor subtypes contribute to TNF-alpha production. We found that superoxide was a critical mediator of T-cell TNF-alpha production, as this was significantly inhibited by polyethylene glycol (PEG)-SOD, but not PEG-catalase. Thus, T cells contain an endogenous renin-angiotensin system that modulates T-cell function, NADPH oxidase activity, and production of superoxide that, in turn, modulates TNF-alpha production. These findings contribute to our understanding of how ANG II and T cells enhance inflammation in cardiovascular disease.
authors.affiliation: Division of Cardiology, the Lowance Center of Human Immunology, Emory University School of Medicine, 1639 Pierce Dr., Atlanta, GA 30322, USA.
authors.forename: Nyssa E
authors.initials: NE
authors.lastname: Hoch
authors.forename: Tomasz J
authors.initials: TJ
authors.lastname: Guzik
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Tenecia
authors.initials: T
authors.lastname: Deans
authors.forename: Samer A
authors.initials: SA
authors.lastname: Maalouf
authors.forename: Petra
authors.initials: P
authors.lastname: Gratze
authors.forename: Cornelia
authors.initials: C
authors.lastname: Weyand
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
mesh_terms: D019264:Adoptive Transfer; D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D001794:Blood Pressure; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D015918:Infusion Pumps, Implantable; D019808:Losartan / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000172:deficiency / Q000235:genetics; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D018398:Homeodomain Proteins; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D014409:Tumor Necrosis Factor-alpha; C070295:catalase-polyethylene glycol; D000808:Angiotensinogen; D013481:Superoxides; D000804:Angiotensin II; C064658:RAG-1 protein; C073402:PD 123319; D011092:Polyethylene Glycols; D002374:Catalase; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D019808:Losartan