Administration of JTE013 abrogates experimental asthma by regulating proinflammatory cytokine production from bronchial epithelial cells

Terashita, Tomomi; Kobayashi, Kazuyuki; Nagano, Tatsuya; Kawa, Yoshitaka; Tamura, Daisuke; Nakata, Kyosuke; Yamamoto, Masatsugu; Tachihara, Motoko; Kamiryo, Hiroshi; Nishimura, Yoshihiro

doi:10.1186/s12931-016-0465-x

Cited by 14 publications

(17 citation statements)

References 48 publications

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“…In the present study, using an S1P 2 antagonist, JTE‐013, and S1P 2 ‐deficient mice, two main findings were obtained in OVA‐induced allergic asthma. Firstly, the S1P 2 receptor functions to exacerbate allergic asthma responses in vivo; this was previously observed using JTE‐013 by Terashita et al (), implying that blockade of the S1P 2 receptor offers a potential strategy for the treatment of allergic asthma. Secondly, the S1P 2 receptor is involved in dendritic cell maturation and migration in the antigen sensitization phase, which is a novel finding.…”

Section: Discussionmentioning

confidence: 68%

Blockage of sphingosine‐1‐phosphate receptor 2 attenuates allergic asthma in mice

Park

2019

British J Pharmacology

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Background and Purpose: Sphingosine-1-phosphate 2 (S1P 2 ) receptors have been implicated in degranulation of mast cells. However, functions of S1P 2 receptors have not been investigated in an in vivo model of allergic asthma.Experimental Approach: Using an ovalbumin (OVA)-induced asthma model, the function of S1P 2 receptors was evaluated in S1P 2 -deficient mice or in mice treated with JTE-013, a selective S1P 2 antagonist. Bone marrow-derived dendritic cells (BMDCs) were used to investigate the roles of S1P 2 receptors in dendritic cell maturation and migration.Key Results: Eosinophil accumulation and elevated Th2 cytokine levels in bronchoalveolar lavage fluid and inflamed lung tissues were strongly inhibited by administration of JTE-013 before OVA sensitization, before OVA challenge, and before both events. In S1P 2 -deficient mice, allergic responses were significantly lower than in wild-type mice. LPS-and OVA-induced maturation of BMDCs was significantly blunted in dendritic cells from S1P 2 -deficient mice and by treatment with JTE-013.Migrations of immature and mature BMDCs were also dependent on S1P 2 receptors.It was found that OVA-challenged mice into which in vitro OVA primed BMDCs from S1P 2 -deficient mice were adoptively transferred, had less severe asthma responses than OVA-challenged mice into which OVA-primed BMDCs from wild-type mice were adoptively transferred.Conclusions and Implications: Pro-allergic functions of S1P 2 receptors were elucidated in a murine asthma model. S1P 2 receptors were involved not only in maturation and migration of dendritic cells in the sensitization phase but also in mast cell degranulation in the challenge phase. These results suggest S1P 2 receptor as a therapeutic target for allergic asthma.

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Section: Discussionmentioning

confidence: 68%

Blockage of sphingosine‐1‐phosphate receptor 2 attenuates allergic asthma in mice

Park

2019

British J Pharmacology

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“…Protein amounts were quantified using the Bradford assay reagent from Bio-Rad (Bio-Rad Laboratories, Hercules, California, USA). Extracts (40 μg) were separated by electrophoresis on a 10-15% denaturing polyacrylamide-SDS gel and electrotransferred to nitrocellulose membranes as previously described (26,28). Membranes were blocked overnight at 4°C with PBS containing 5% w/v nonfat dry milk and 0.1% Tween-20, washed three times with PBS containing 0.1% Tween-20 and then incubated with specific primary antibodies against EDG-1 (S1PR-1), EDG-3 (S1PR-3), EDG-5 (S1PR-2) (Santa Cruz Biotechnology, Santa Cruz, CA, USA), GAPDH and cleaved-caspase 3 (Cell Signaling Technology, Danvers, MA) at a dilution of 1:1000 in PBS containing 5% w/v BSA and 0.1% Tween-20.…”

Section: Western Blotmentioning

confidence: 99%

Inhibition of the sphingosine‐1‐phosphate pathway promotes the resolution of neutrophilic inflammation

et al. 2019

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Sphingosine-1-phosphate (S1P) is an important sphingolipid derived from plasma membrane and has a known role in productive phase of inflammation, but its role in neutrophil survival and resolution phase of inflammation is unknown. Here, we investigated the effects of inhibition of S1P receptors and the blockade of S1P synthesis in BALB/c mice and human neutrophils. S1P and S1PR1-3 receptors expression were increased in cells from the pleural cavity stimulated with LPS. Using different antagonists of S1PRs and inhibitors of different steps of the metabolic pathway of S1P production, we show that S1P and its receptors are involved in regulating neutrophil survival and resolution of inflammation in the pleural cavity. Given the role of the S1P-S1PR axis in resolution of inflammation, we sought to identify whether blockade at different levels of the sphingosine-1-phosphate synthesis pathway could affect neutrophil survival in vitro. Inhibitors of the S1P pathway were also able to induce human neutrophil apoptosis. In addition, blockade of S1P synthesis or its receptor facilitated the efferocytosis of apoptotic neutrophil. Taken together, our data demonstrate a fundamental role for S1P in regulating the outcome of inflammatory responses, and position S1P-S1PR axis as a potential target for treatment of neutrophilic inflammation.

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“…Total cellular RNA preparation from BEAS-2B and Calu-3 before and after S1P stimulation was performed as described [ 8 , 9 ]. Total RNA labeled with Cy3 or Cy5 was hybridized to a 3D-Gene Human Oligo chip 25 k (Toray Industries Inc., Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…Relative human mRNA levels were calculated with the ΔΔCt method using the glyceraldehyde 3-phosphate dehydrogenase ( GAPDH ) mRNA as an internal control. The primers used in this study are as followed: and for GAPDH [ 14 ], and for CCL3 [ 9 ], and for TIMP2 [ 9 ], and for IL-8 [ 15 ], and for S1PR3 [ 16 ], and and for CCL20 [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…We showed that PLCεis expressed in the bronchial epithelial cells (ECs) and has a role in asthma through upregulating the inflammatory cytokine production by the bronchial ECs in the elicitation phase [ 8 ]. In addition, we found that S1PR1-3 expressed on mouse airway ECs and S1PR2 had a role in nuclear factorκB (NF-κB) activation and CC chemokine ligand 3 (CCL) 3 production in the bronchial ECs [ 9 ]. However, JTE013, S1PR2 antagonist did not completely attenuate the ovalbumin (OVA)-induced airway inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Role of S1P/S1PR3 axis in release of CCL20 from human bronchial epithelial cells

et al. 2018

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BackgroundSphingosine kinase phosphorylates sphingosine to generate sphingosine 1 phosphate (S1P) following stimulation of the five plasma membrane G-protein-coupled receptors. The objective of this study is to clarify the role of S1P and its receptors (S1PRs), especially S1PR3 in airway epithelial cells.MethodsThe effects of S1P on asthma-related genes expression were examined with the human bronchial epithelial cells BEAS-2B and Calu-3 using a transcriptome analysis and siRNA of S1PRs. To clarify the role of CCL20 in the airway inflammation, BALB/c mice were immunized with ovalbumin (OVA) and subsequently challenged with an OVA-containing aerosol to induce asthma with or without intraperitoneal administration of anti-CCL20. Finally, the anti-inflammatory effect of VPC 23019, S1PR1/3 antagonist, in the OVA-induced asthma was examined.ResultsS1P induced the expression of some asthma-related genes, such as ADRB2, PTGER4, and CCL20, in the bronchial epithelial cells. The knock-down of SIPR3 suppressed the expression of S1P-inducing CCL20. Anti-CCL20 antibody significantly attenuated the eosinophil numbers in the bronchoalveolar lavage fluid (P<0.01). Upon OVA challenge, VPC23019 exhibited substantially attenuated eosinophilic inflammation.ConclusionsS1P/S1PR3 pathways have a role in release of proinflammatory cytokines from bronchial epithelial cells. Our results suggest that S1P/S1PR3 may be a possible candidate for the treatment of bronchial asthma.

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Administration of JTE013 abrogates experimental asthma by regulating proinflammatory cytokine production from bronchial epithelial cells

Cited by 14 publications

References 48 publications

Blockage of sphingosine‐1‐phosphate receptor 2 attenuates allergic asthma in mice

Blockage of sphingosine‐1‐phosphate receptor 2 attenuates allergic asthma in mice

Inhibition of the sphingosine‐1‐phosphate pathway promotes the resolution of neutrophilic inflammation

Role of S1P/S1PR3 axis in release of CCL20 from human bronchial epithelial cells

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