Thromboxane A synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand

Matsunobu, Takehiko; Okuno, Toshiaki; Yokoyama, Chieko; Yokomizo, Takehiko

doi:10.1194/jlr.m037754

Cited by 60 publications

(54 citation statements)

References 31 publications

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“…3 B ) in agreement with a prior report (28). Because 12‐HHT, an endogenous ligand for BLT2, is produced during blood coagulation by activated platelets (41), FCS contains about 300 nM 12‐HHT. Therefore, BLT2 is constantly activated in culture medium containing 10% FCS.…”

Section: Resultsmentioning

confidence: 99%

Leukotriene B₄receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins

et al. 2015

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GPCRs are involved in numerous physiologic functions and are important drug targets. Although the epithelial barrier is important for protection from invading pathogens, the correlation between GPCRs and epithelial barrier function remains unknown. Leukotriene B 4 (LTB 4 ) receptor type 2 (BLT2), mainly expressed in epithelial cells, is a GPCR for 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB 4 . In our study, BLT2 localized at the lateral membrane in BLT2-overexpressing Madin-Darby canine kidney (MDCK) II cells and in the small intestine of BLT2-transgenic mice. BLT2-deficient mice exhibited higher transepidermal water loss and were more sensitive to epicutaneous sensitization. MDCK-BLT2 cells recovered transepithelial electrical resistance (TER) after a calcium switch faster than did MDCK-Mock cells, and 12-HHT stimulation accelerated TER recovery only in MDCK-BLT2 cells. Quantitative PCR and immunoblot analyses revealed that the 12-HHT/ BLT2 axis up-regulated claudin-4 (CLDN4) expression in MDCK-BLT2 cells and human primary keratinocytes, and CLDN4 knockdown abolished 12-HHT-dependent TER recovery. Acceleration of TER recovery and induction of CLDN4 expression by 12-HHT stimulation were abolished by inhibition of Ga i protein or p38 MAPK. These results show that 12-HHT/BLT2 enhances epithelial barrier function by increasing CLDN4 expression via the Ga i protein-p38 MAPK pathway.-Ishii, Y

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Section: Resultsmentioning

confidence: 99%

Leukotriene B₄receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins

et al. 2015

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“…After drying the cartridge, eicosanoids were eluted by centrifugation with 200 μl of 0.1% formic acid in methanol. For reverse phase-HPLC-MS/MS, a Shimadzu liquid chromatography system consisting of four LC-20AD pumps, a SIL-20AC autosampler, a CTO-20AC column oven, a FCV-12AH six-port switching valve, and a TSQ Quantum Ultra triple quadrupole mass spectrometer equipped with an electrospray ionization (ESI) ion source (Thermo Fisher Scientific) were used (91,92). An aliquot of each sample (50 μl) was injected into the trap column, an Opti-Guard Mini C18 (Optimize Technologies), at a total flow rate of 500 μl/min.…”

Section: Methodsmentioning

confidence: 99%

Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models

Sasaki¹,

Koga²,

Ohba³

et al. 2018

JCI Insight

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Age-related macular degeneration (AMD), a progressive chronic disease of the central retina, is associated with aging and is a leading cause of blindness worldwide. Here, we demonstrate that leukotriene B4 (LTB4) receptor 1 (BLT1) promotes laser-induced choroidal neovascularization (CNV) in a mouse model for wet-type AMD. CNV was significantly less in BLT1-deficient (BLT1-KO) mice compared with BLT1-WT controls. Expression of several proangiogenic and profibrotic factors was lower in BLT1-KO eyes than in BLT1-WT eyes. LTB4 production in the eyes was substantially increased in the early phase after laser injury. BLT1 was highly expressed in M2 macrophages in vitro and in vivo, and ocular BLT1+ M2 macrophages were increased in the aged eyes after laser injury. Furthermore, M2 macrophages were rapidly attracted by LTB4 and subsequently produced VEGF-A- through BLT1-mediated signaling. Consequently, intravitreal injection of M2 macrophages augmented CNV formation, which was attenuated by BLT1 deficiency. Thus, laser-induced injury to the retina triggered LTB4 production and attracted M2 macrophages via BLT1, leading to development of CNV. A selective BLT1 antagonist (CP105696) and 3 LTB4 inhibitors (zileuton, MK-886, and bestatin) reduced CNV in a dose-dependent manner. CP105696 also inhibited the accumulation of BLT1+ M2 macrophages in the laser-injured eyes of aged mice. Together, these results indicate that the LTB4-BLT1 axis is a potentially novel therapeutic target for CNV of wet-type AMD.

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“…5 × 10 6 RAW cells/100-mm dish were plated and cultured for 24 h (day 1), 48 h (day 2) and 72 h (day 3). (21). An aliquot of each sample (50 µL) was injected into the trap column, an Opti-Guard Mini C18, at a total flow rate of 500 µL/min.…”

Section: Methodsmentioning

confidence: 99%

Altered eicosanoid production and phospholipid remodeling during cell culture

Okuno

Gijón

Zarini

et al. 2018

Journal of Lipid Research

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Thromboxane A synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand

Cited by 60 publications

References 31 publications

Leukotriene B₄receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins

Leukotriene B₄receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins

Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models

Altered eicosanoid production and phospholipid remodeling during cell culture

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Thromboxane A synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand

Cited by 60 publications

References 31 publications

Leukotriene B4receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins

Leukotriene B4receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins

Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models

Altered eicosanoid production and phospholipid remodeling during cell culture

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Product

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Leukotriene B₄receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins

Leukotriene B₄receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins