title: Angiotensin II Type-2 receptors modulate inflammation through signal transducer and activator of transcription proteins 3 phosphorylation and TNFα production.
abstract: Angiotensin subtype-1 receptor (AT(1)R) influences inflammatory processes through enhancing signal transducer and activator of transcription proteins 3 (STAT3) signal transduction, resulting in increased tumor necrosis factor-α (TNF-α) production. Although angiotensin subtype-2 receptor (AT(2)R), in general, antagonizes AT(1)R-stimulated activity, it is not known if AT(2)R has any anti-inflammatory effects. In this study, we tested the hypothesis that AT(2)R activation plays an anti-inflammatory role by reducing STAT3 phosphorylation and TNF-α production. Changes in AT(2)R expression, TNF-α production, and STAT3 phosphorylation were quantified by Western blotting, Bio-Plex cytokine, and phosphoprotein cellular signaling assays in PC12W cells that express AT(2)R but not AT(1)R, in response to the AT(2)R agonist, CGP-42112 (CGP, 100 nm), or AT(2)R antagonist PD-123319 (PD, 1 μm). A 100% increase in AT(2)R expression in response to stimulation with its agonist CGP was observed. Further, AT(2)R activation reduced TNF-α production by 39% and STAT3 phosphorylation by 83%. In contrast, PD decreased AT(2)R expression by 76%, increased TNF-α production by 84%, and increased STAT3 phosphorylation by 67%. These findings suggest that increased AT(2)R expression may play a role in the observed decrease in inflammatory pathway activation through decreased TNF-α production and STAT3 signaling. Restoration of AT(2)R expression and/or its activation constitute a potentially novel therapeutic target for the management of inflammatory processes.
authors.affiliation: Division of Geriatric Medicine and Gerontology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Abadir
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Walston
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
authors.forename: Helmy M
authors.initials: HM
authors.lastname: Siragy
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D056747:Immunomodulation; D007249:Inflammation; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D009842:Oligopeptides; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; C060894:CGP 42112A; C073402:PD 123319