title: The critical role of IL-1 receptor-associated kinase 4-mediated NF-κB activation in modified low-density lipoprotein-induced inflammatory gene expression and atherosclerosis.
abstract: Exciting discoveries related to IL-1R/TLR signaling in the development of atherosclerosis plaque have triggered intense interest in the molecular mechanisms by which innate immune signaling modulates the onset and development of atherosclerosis. Previous studies have clearly shown the definitive role of proinflammatory cytokine IL-1 in the development of atherosclerosis. Recent studies have provided direct evidence supporting a link between innate immunity and atherogenesis. Although it is still controversial about whether infectious pathogens contribute to cardiovascular diseases, direct genetic evidence indicates the importance of IL-1R/TLR signaling in atherogenesis. In this study, we examined the role of IL-1R-associated kinase 4 (IRAK4) kinase activity in modified low-density lipoprotein (LDL)-mediated signaling using bone marrow-derived macrophage as well as an in vivo model of atherosclerosis. First, we found that the IRAK4 kinase activity was required for modified LDL-induced NF-κB activation and expression of a subset of proinflammatory genes but not for the activation of MAPKs in bone marrow-derived macrophage. IRAK4 kinase-inactive knockin (IRAK4KI) mice were bred onto ApoE(-/-) mice to generate IRAK4KI/ApoE(-/-) mice. Importantly, the aortic sinus lesion formation was impaired in IRAK4KI/ApoE(-/-) mice compared with that in ApoE(-/-) mice. Furthermore, proinflammatory cytokine production was reduced in the aortic sinus region of IRAK4KI/ApoE(-/-) mice compared with that in ApoE(-/-) mice. Taken together, our results indicate that the IRAK4 kinase plays an important role in modified LDL-mediated signaling and the development of atherosclerosis, suggesting that pharmacological inhibition of IRAK4 kinase activity might be a feasible approach in the development of antiatherosclerosis drugs.
authors.affiliation: Department of Immunology, Learner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Tae Whan
authors.initials: TW
authors.lastname: Kim
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Peggy
authors.initials: P
authors.lastname: Robinet
authors.forename: Brandon
authors.initials: B
authors.lastname: Dugar
authors.forename: Diane
authors.initials: D
authors.lastname: Greene
authors.forename: Anna
authors.initials: A
authors.lastname: Cerny
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Raymond
authors.initials: R
authors.lastname: Gilmour
authors.forename: Kirk
authors.initials: K
authors.lastname: Staschke
authors.forename: Guy
authors.initials: G
authors.lastname: Chisolm
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
authors.forename: Paul E
authors.initials: PE
authors.lastname: DiCorleto
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000107:Acetylation; D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D008078:Cholesterol, LDL / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000008:administration & dosage* / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000008:administration & dosage* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology
chemical_list: D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases