title: Angiotensin AT2 receptor stimulation is anti-inflammatory in lipopolysaccharide-activated THP-1 macrophages via increased interleukin-10 production.
abstract: Macrophages have an important role in the pathogenesis of hypertension and associated end-organ damage via the activation of the Toll-like receptors, such as Toll-like receptor-4 (TLR4). Accumulating evidence suggests that the angiotensin AT2 receptor (AT2R) has a protective role in pathological conditions involving inflammation and tissue injury. We have recently shown that AT(2)R stimulation is renoprotective, which occurs in part via increased levels of anti-inflammatory interleukin-10 (IL-10) production in renal epithelial cells; however, the role of AT(2)R in the inflammatory activity of macrophages is not known. The present study was designed to investigate whether AT(2)R activation stimulates an anti-inflammatory response in TLR4-induced inflammation. The effects of the anti-inflammatory mechanisms that occurred following pre-treatment with the AT(2)R agonist Compound 21 (C21) (1 μmol ml(-1)) on the cytokine profiles of THP-1 macrophages after activation by lipopolysaccharide (LPS) (1 μg ml(-1)) were studied. The AT(2)R agonist dose-dependently attenuated LPS-induced tumor necrosis factor-α (TNF-α) and IL-6 production but increased IL-10 production. IL-10 was critical for the anti-inflammatory effects of AT(2)R stimulation because the IL-10-neutralizing antibody dose-dependently abolished the AT(2)R-mediated decrease in TNF-α levels. Further, enhanced IL-10 levels were associated with a sustained, selective increase in the phosphorylation of extracellular signal-regulated kinase (ERK1/2) but not p38 mitogen-activated protein kinase (MAPK). Blocking the activation of ERK1/2 before C21 pre-treatment completely abrogated this increased IL-10 production in response to the AT(2)R agonist C21, while there was a partial reduction in IL-10 levels following the inhibition of p38. We conclude that AT(2)R stimulation exerts a novel anti-inflammatory response in THP-1 macrophages via enhanced IL-10 production as a result of sustained, selective ERK1/2 phosphorylation, which may have protective roles in hypertension and associated tissue injury.
authors.affiliation: 1] Department of Pharmacological and Pharmaceutical Sciences, Heart and Kidney Institute, University of Houston, Houston, TX, USA [2] Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Isha
authors.initials: I
authors.lastname: Dhande
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Wanshu
authors.initials: W
authors.lastname: Ma
authors.affiliation: 1] Department of Pharmacological and Pharmaceutical Sciences, Heart and Kidney Institute, University of Houston, Houston, TX, USA [2] Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Tahir
authors.initials: T
authors.lastname: Hussain
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D016753:Interleukin-10 / Q000378:metabolism*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000378:metabolism; D013777:Tetrazoles; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C508609:IL10 protein, human; D008070:Lipopolysaccharides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C081643:candesartan