title: Losartan inhibits LPS + ATP-induced IL-1beta secretion from mouse primary macrophages by suppressing NALP3 inflammasome.
abstract: OBJECTIVE
  IL-1beta is a potent proinflammatory, pro-fibrogenetic and pro-athrosclerosis cytokine which has been shown to play an important role in an expanding number of noninfectious, chronic inflammatory conditions including cardiovascular disease, renal fibrosis, rheumatoid arthritis and even type 2 diabetes. Losartan is an angiotensin II receptor antagonist widely used for the treatment of hypertension, diabetic nephropathy and congestive heart failure. In this study, we attempted to clarify whether losartan has an inhibitory effect on IL-1beta. To further elucidate the molecular mechanism underlying the anti-IL-1beta property of losartan, we studied the LPS+ATP-induced activation of NALP3 inflammasome which controls the muturation and secretion of IL-1beta.
  
  
  METHODS
  LPS and ATP were used to stimulate the release of IL-1beta from thioglycollate-elicited macrophages from BALB/c mice. The production of IL-1beta was evaluated by ELISA assay and NALP3, caspase-1, IL-beta mRNA levels were determined by reverse transcription-polymerase chain reaction.
  
  
  RESULTS
  In cultured thioglycollate-elicited macrophages, we observed that LPS + ATP greatly enhanced IL-1 beta secretion (6938.00 +/- 83.45; P < 0.05) and the mRNA levels of NALP3, caspase-1 which are two main components of NALP3 inflammasome (60.88 +/- 8.28; 1.31 +/- 0.04, P < 0.05 for both). The macrophages co-cultured with losartan showed low production of IL-1beta (3907.50 +/- 143.61; P < 0.05) and low production of NALP3, caspase-1mRNA (29.82 +/- 6.92; 1.12 +/- 0.05, P < 0.05 for both). Losartan did not reduce IL-1beta mRNA(P > 0.05).
  
  
  CONCLUSIONS
  Our results show that the NALP3 inflammasome is up-regulated and activated in the mouse macrophage in response to LPS + ATP stimulation. Losartan is able to suppress the LPS + ATP-induced production of IL-1beta protein. In addition, this effectmay be partially mediated by suppressing NALP3 inflammasome activation.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.forename: Zhang-Zhe
authors.initials: ZZ
authors.lastname: Peng
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Tang
authors.forename: Miao-Miao
authors.initials: MM
authors.lastname: Lu
authors.forename: Yu
authors.initials: Y
authors.lastname: Peng
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Mel
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Mo
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.forename: Li-Jian
authors.initials: LJ
authors.lastname: Tao
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology*; D020170:Caspase 1 / Q000096:biosynthesis; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D007111:Immunity, Cellular / Q000187:drug effects; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002352:Carrier Proteins; D018076:DNA, Complementary; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D020170:Caspase 1; D019808:Losartan