title: Losartan inhibits LPS-induced inflammatory signaling through a PPARgamma-dependent mechanism in human THP-1 macrophages.
abstract: Macrophages have critical roles in the pathogenesis of atherosclerosis by activating the innate immune system and producing inflammatory cytokines. Accumulating evidence indicates that angiotensin type 1 receptor (AT1R) blockers exert anti-inflammatory effects in inflammatory diseases including atherosclerosis. In this study, we investigated the effect of losartan, an AT1R blocker, on the proinflammatory gene expression induced by bacterial lipopolysaccharide (LPS) in a well-defined in vitro human THP-1 macrophage system. We found that losartan significantly attenuated the LPS-induced expression of proinflammatory genes TNF-alpha, IL-8 and COX-2. However, exogenous angiotensin II (AngII) had no effect on LPS-induced inflammatory signaling despite the expression of AT1R. In addition, losartan did not block LPS-induced IkappaB phosphorylation, which is downstream of Toll-like receptor activation. Peroxisome proliferator-activated receptor-gamma (PPARgamma) antagonists, GW9662 and T0070907, reversed the inhibitory effects of losartan on LPS-induced TNF-alpha and IL-8 expression in THP-1 macrophages. These observations suggest that losartan inhibits LPS-induced proinflammatory gene expression in macrophages by activating the PPARgamma pathway rather than by the competitive inhibition of AT1R binding to AngII.
authors.affiliation: Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Jianbo
authors.initials: J
authors.lastname: An
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
authors.forename: Keiji
authors.initials: K
authors.lastname: Kuba
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000808:Angiotensinogen / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin; D019808:Losartan