Administration of JTE013 abrogates experimental asthma by regulating proinflammatory cytokine production from bronchial epithelial cells. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Terashita, Tomomi; Kobayashi, Kazuyuki; Nagano, Tatsuya; Kawa, Yoshitaka; Tamura, Daisuke; Nakata, Kyosuke; Yamamoto, Masatsugu; Tachihara, Motoko; Kamiryo, Hiroshi; Nishimura, Yoshihiro
• Is Part Of: Respiratory research. Volume 17:Issue 1(2016)
• Page Start: 1
• Page End: 8
• Publication Date: 2016-12
• Subjects: Sphingosine-1-phosphate -- epithelial cells -- BEAS-2B -- JTE013 -- CCL3; Respiratory organs -- Diseases -- Periodicals; 616.2005
• DOI: 10.1186/s12931-016-0465-x
• Languages: English
• ISSNs: 1465-993X

Abstract

Abstract Background Sphingosine-1-phosphate (S1P) is a bioactive phospholipid that acts as a signal transducer by binding to S1P receptors (S1PR) 1 to 5. The S1P/S1PRs pathway has been associated with remodeling and allergic inflammation in asthma, but the expression pattern of S1PR and its effects on non-immune cells have not been completely clarified. The aim of this study was to examine the contribution of the signaling of S1P and S1PRs expressed in airway epithelial cells (ECs) to asthma responses in mice. Methods Bronchial asthma was experimentally induced in BALB/c mice by ovalbumin (OVA) sensitization followed by an OVA inhalation challenge. The effects of S1PR antagonists on the development of asthma were analyzed 24 h after the OVA challenge. Results Immunohistological analysis revealed S1PR1-3 expression on mouse airway ECs. Quantitative real-time polymerase chain reaction demonstrated that S1P greatly stimulated the induction ofCCL3 andTIMP2 mRNA in human airway ECs, i.e., BEAS-2B cells, in a dose-dependent manner. Pretreatment with the S1PR2 antagonist JTE013 inhibited theCCL3 gene expression in BEAS-2B cells. Immunohistological analysis also showed that the expression level ofCCL3 was attenuated by JTE013 in asthmatic mice. Furthermore, JTE013 as well as anti-CCL3 antibody attenuated allergic responses. Intratracheal administration of JTE013 also attenuated eosinophilic reactions in bronchoalveolar lavage fluids. S1P induced transcription factor NFκB activation, while JTE013 greatly reduced the NFκB activation. Conclusions JTE013 attenuated allergic airway reactions by regulating CCL3 production from bronchial ECs. The intratracheal administration of JTE013 may be a promising therapeutic strategy for bronchial asthma.