title: 5-Lipoxygenase plays an essential role in 4-HNE-enhanced ROS production in murine macrophages via activation of NADPH oxidase.
abstract: 4-Hydroxynonenal (HNE) mediates oxidative stress-linked pathological processes; however, its role in the generation of reactive oxygen species (ROS) in macrophages is still unclear. Thus, this study investigated the sources and mechanisms of ROS generation in macrophages stimulated with HNE. Exposure of J774A.1 cells to HNE showed an increased production of ROS, which was attenuated by NADPH oxidase as well as 5-lipoxygenase (5-LO) inhibitors. Linked to these results, HNE increased membrane translocation of p47phox promoting NADPH oxidase activity, which was attenuated in peritoneal macrophages from 5-LO-deficient mice as well as in J774A.1 cells treated with a 5-LO inhibitor, MK886 or 5-LO siRNA. In contrast, HNE-enhanced 5-LO activity was not affected by inhibition of NADPH oxidase. Furthermore, leukotriene B(4), 5-LO metabolite, was found to enhance NADPH oxidase activity in macrophages. Altogether, these results suggest that 5-LO plays a critical role in HNE-induced ROS generation in murine macrophages through activation of NADPH oxidase.
authors.affiliation: MRC for Ischemic Tissue Regeneration, Pusan National University, Busan, Korea.
authors.forename: Mi R
authors.initials: MR
authors.lastname: Yun
authors.forename: Hye M
authors.initials: HM
authors.lastname: Park
authors.forename: Kyo W
authors.initials: KW
authors.lastname: Seo
authors.forename: Seung J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Dong S
authors.initials: DS
authors.lastname: Im
authors.forename: Chi D
authors.initials: CD
authors.lastname: Kim
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D015289:Leukotrienes / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D002722:Chlorobenzenes
chemical_list: D000447:Aldehydes; D001094:Arachidonate 5-Lipoxygenase; D007211:Indoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D019255:NADPH Oxidases; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C060893:MK-886; D002722:Chlorobenzenes; C060505:neutrophil cytosolic factor 1; C027576:4-hydroxy-2-nonenal