title: Modulation of leukotriene B4 receptor 1 signaling by receptor for advanced glycation end products (RAGE).
abstract: Leukotriene B4 (LTB4) receptor 1 (BLT1), a high-affinity GPCR for LTB4, plays important roles in acute and chronic inflammatory diseases. Although the LTB4-BLT1 axis is known to promote inflammation, no studies have defined the binding proteins that modulate LTB4-BLT1 signaling. In this study, the receptor for advanced glycation end products (RAGE) interacted with BLT1 in human cervical epithelial HeLa cells. RAGE increased LTB4-BLT1-dependent ERK phosphorylation and inhibited LTB4-BLT1-dependent activation of NF-κB and up-regulation of proinflammatory cytokines and chemokines. RAGE-dependent inhibition of NF-κB was blunted by treatment with an MEK inhibitor, suggesting that RAGE suppresses LTB4-BLT1-dependent NF-κB signaling by enhancing the MEK-ERK pathway. Meanwhile, in a chemotaxis assay of mouse bone marrow-derived neutrophils, the velocity of LTB4-dependent neutrophil migration was attenuated by soluble RAGE, which is an inhibitory decoy protein for RAGE signaling, in a dose-dependent manner (0.2-5 μg/ml), or by RAGE deficiency. Furthermore, both LTB4-dependent ERK phosphorylation in neutrophils and LTB4-dependent neutrophil accumulation in a murine peritonitis model were significantly attenuated in RAGE-deficient mice compared with C57BL/6J wild-type mice, indicating that RAGE potentiates LTB4-dependent neutrophil migration by enhancing ERK phosphorylation. Our results demonstrate that RAGE interacts with BLT1 and modulates LTB4-BLT1 signaling through potentiation of the MEK-ERK pathway.-Ichiki, T., Koga, T., Okuno, T., Saeki K., Yamamoto, Y., Yamamoto, H., Sakaguchi, M., Yokomizo, T. Modulation of leukotriene B4 receptor 1 signaling by receptor for advanced glycation end products (RAGE).
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan;
authors.forename: Takako
authors.initials: T
authors.lastname: Ichiki
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan; tkoga@juntendo.ac.jp.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan;
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan;
authors.forename: Kazuko
authors.initials: K
authors.lastname: Saeki
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan; and.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan; and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan; yokomizotky@umin.ac.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokomizo
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C000593873:Ager protein, mouse; D000951:Antigens, Neoplasm; C513240:LTB4R protein, human; C503704:Ltb4r1 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D018102:Receptors, Leukotriene B4; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D002118:Calcium
keywords: GPCR; chemotaxis; lipid mediator