Modulation of leukotriene B4 receptor 1 signaling by receptor for advanced glycation end products (RAGE)

Takako Ichiki, Tomoaki Koga, Toshiaki Okuno, Kazuko Saeki, Yasuhiko Yamamoto, Hiroshi Yamamoto, Masakiyo Sakaguchi, Takehiko Yokomizo

Research output: Contribution to journalArticle

12 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)1811-1822
Number of pages12
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume30
Issue number5
DOIs
Publication statusPublished - May 1 2016

Fingerprint

Leukotriene B4 Receptors
Leukotriene B4
Modulation
Neutrophils
Phosphorylation
Mitogen-Activated Protein Kinase Kinases
MAP Kinase Signaling System
Advanced Glycosylation End Product-Specific Receptor
Chemotaxis
Peritonitis
HeLa Cells
Chemokines

Keywords

  • chemotaxis
  • GPCR
  • lipid mediator

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Modulation of leukotriene B4 receptor 1 signaling by receptor for advanced glycation end products (RAGE). / Ichiki, Takako; Koga, Tomoaki; Okuno, Toshiaki; Saeki, Kazuko; Yamamoto, Yasuhiko; Yamamoto, Hiroshi; Sakaguchi, Masakiyo; Yokomizo, Takehiko.

In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 30, No. 5, 01.05.2016, p. 1811-1822.

Research output: Contribution to journalArticle

Ichiki, Takako ; Koga, Tomoaki ; Okuno, Toshiaki ; Saeki, Kazuko ; Yamamoto, Yasuhiko ; Yamamoto, Hiroshi ; Sakaguchi, Masakiyo ; Yokomizo, Takehiko. / Modulation of leukotriene B4 receptor 1 signaling by receptor for advanced glycation end products (RAGE). In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2016 ; Vol. 30, No. 5. pp. 1811-1822.
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