title: Candesartan reduces the innate immune response to lipopolysaccharide in human monocytes.
abstract: OBJECTIVE
  Inhibition of angiotensin II receptor type 1 (AT1) reduces chronic inflammation associated with hypertension. We asked whether AT1 receptor inhibition would reduce the innate inflammatory response induced by bacterial lipopolysaccharide (LPS).
  
  
  METHODS
  We used unstimulated human circulating monocytes obtained from healthy donors by counterflow centrifugal elutriation. Monocytes were studied in vitro after incubation with LPS (50 ng/ml) with and without 1 mumol/l candesartan, an AT1 receptor blocker. Angiotensin II receptor mRNA expression was determined by reverse transcriptase-PCR and receptor binding by autoradiography; inflammatory factor mRNA expression was studied by reverse transcriptase-PCR and cytokine release by ELISA.
  
  
  RESULTS
  Human monocytes did not express detectable AT1 receptors, and angiotensin II did not induce inflammatory factor mRNA expression or cytokine release. However, candesartan substantially reduced the LPS-induced expression of the mRNAs for the LPS recognition protein cluster of differentiation 14, the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1 beta and interleukin-6 and the lectin-like oxidized low-density lipoprotein receptor. In addition, candesartan reduced the activation of the nuclear factor kappa B pathway, the tumor necrosis factor alpha and interleukin-6 secretion, and the ROS formation induced by LPS, without affecting the secretion of interleukin-10.
  
  
  CONCLUSIONS
  We hypothesize that the anti-inflammatory effects of candesartan in these cells are likely mediated by mechanisms unrelated to AT1 receptor blockade. Our results demonstrate that candesartan significantly reduces the innate immune response to LPS in human circulating monocytes. The anti-inflammatory effects of candesartan may be of importance not only in hypertension but also in other inflammatory disorders.
authors.affiliation: Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Ignacio M
authors.initials: IM
authors.lastname: Larrayoz
authors.forename: Tao
authors.initials: T
authors.lastname: Pang
authors.forename: Julius
authors.initials: J
authors.lastname: Benicky
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Pavel
authors.forename: Enrique
authors.initials: E
authors.lastname: Sánchez-Lemus
authors.forename: Juan M
authors.initials: JM
authors.lastname: Saavedra
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004359:Drug Therapy, Combination; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C081643:candesartan