title: 5-Lipoxygenase plays a pivotal role in endothelial adhesion of monocytes via an increased expression of Mac-1.
abstract: OBJECTIVE
  5-Lipoxygenase (5-LO) is known to participate in the pathogenesis of atherosclerosis; however, the underlying mechanisms are unclear. Thus, this study investigated the molecular mechanisms responsible for 5-LO expression in monocytes as well as the role of 5-LO in monocyte adhesion to the vascular endothelium, which is a key early event in macrophage foam cell formation.
  
  
  RESULTS
  An en face immunohistochemistry of endothelial surfaces revealed a marked increase in monocyte adhesion to the aortic endothelium in wild-type (WT) mice treated with lipopolysaccharide (LPS), which was significantly attenuated in 5-LO((-/-)) mice. Likewise, the adhesion capacity of primary monocytes isolated from LPS-treated WT mice was higher than those of monocytes from 5-LO((-/-)) mice. In in vitro study, LPS increased monocyte adhesion to endothelial cells with an enhanced Mac-1 expression. These were attenuated by a 5-LO inhibitor, MK886, as well as by molecular depletion of 5-LO in monocytes. Furthermore, LPS-induced Mac-1 expression on monocytes was significantly inhibited by pre-treatment with U-75302, a BLT1-receptor antagonist, suggesting a pivotal role of 5-LO-derived leukotrienes. In promoter activity analysis and chromatin immunoprecipitation assays to identify transcription factors involved in 5-LO expression, both NF-κB and Sp1 played central roles to increase 5-LO expression in LPS-treated monocytes.
  
  
  CONCLUSIONS
  5-LO expression in monocytes is modulated via NF-κB and Sp1 signalling pathways, and 5-LO plays a pivotal role in LPS-mediated monocyte adhesion to the vascular endothelium through an increased expression of Mac-1 on monocytes.
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Choi
authors.forename: Kyo Won
authors.initials: KW
authors.lastname: Seo
authors.forename: Jin Ung
authors.initials: JU
authors.lastname: Bae
authors.forename: Yun Hak
authors.initials: YH
authors.lastname: Kim
authors.forename: So Youn
authors.initials: SY
authors.lastname: Park
authors.forename: Sae Ock
authors.initials: SO
authors.lastname: Oh
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D018102:Receptors, Leukotriene B4 / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
chemical_list: C513240:LTB4R protein, human; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D018102:Receptors, Leukotriene B4; D016329:Sp1 Transcription Factor; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D001094:Arachidonate 5-Lipoxygenase
keywords: 5-Lipoxygenase; Mac-1; Monocyte adhesion; TLR4; Vascular inflammation