Browse > Article
http://dx.doi.org/10.4062/biomolther.2020.206

Suppressive Effect of CYM50358 S1P4 Antagonist on Mast Cell Degranulation and Allergic Asthma in Mice  

Jeon, Wi-Jin (College of Pharmacy, Pusan National University)
Chung, Ki Wung (College of Pharmacy, Pusan National University)
Lee, Joon-Hee (College of Pharmacy, Pusan National University)
Im, Dong-Soon (College of Pharmacy, Pusan National University)
Publication Information
Biomolecules & Therapeutics / v.29, no.5, 2021 , pp. 492-497 More about this Journal
Abstract
Levels of sphingosine 1-phosphate (S1P), an intercellular signaling molecule, reportedly increase in the bronchoalveolar lavage fluids of patients with asthma. Although the type 4 S1P receptor, S1P4 has been detected in mast cells, its functions have been poorly investigated in an allergic asthma model in vivo. S1P4 functions were evaluated following treatment of CYM50358, a selective antagonist of S1P4, in an ovalbumin-induced allergic asthma model, and antigen-induced degranulation of mast cells. CYM50358 inhibited antigen-induced degranulation in RBL-2H3 mast cells. Eosinophil accumulation and an increase of Th2 cytokine levels were measured in the bronchoalveolar lavage fluid and via the inflammation of the lungs in ovalbumin-induced allergic asthma mice. CYM50358 administration before ovalbumin sensitization and before the antigen challenge strongly inhibited the increase of eosinophils and lymphocytes in the bronchoalveolar lavage fluid. CYM50358 administration inhibited the increase of IL-4 cytokines and serum IgE levels. Histological studies revealed that CYM50358 reduced inflammatory scores and PAS (periodic acid-Schiff)-stained cells in the lungs. The pro-allergic functions of S1P4 were elucidated using in vitro mast cells and in vivo ovalbumin-induced allergic asthma model experiments. These results suggest that S1P4 antagonist CYM50358 may have therapeutic potential in the treatment of allergic asthma.
Keywords
$S1P_4$; Sphingosine 1-phosphate; Anti-allergic; Anti-asthmatic; Degranulation; Mast cell;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Park, S. J. and Im, D. S. (2020) Blockage of sphingosine-1-phosphate receptor 2 attenuates 2,4-dinitrochlorobenzene-induced atopic dermatitis in mice. Acta Pharmacol. Sin. 41, 1487-1496.   DOI
2 Prieschl, E. E., Csonga, R., Novotny, V., Kikuchi, G. E. and Baumruker, T. (1999) The balance between sphingosine and sphingosine1-phosphate is decisive for mast cell activation after Fcɛ receptor I triggering. J. Exp. Med. 190, 1-8.   DOI
3 Onuma, T., Tanabe, K., Kito, Y., Tsujimoto, M., Uematsu, K., Enomoto, Y., Matsushima-Nishiwaki, R., Doi, T., Nagase, K., Akamatsu, S., Tokuda, H., Ogura, S., Iwama, T., Kozawa, O. and Iida, H. (2017) Sphingosine 1-phosphate (S1P) suppresses the collagen-induced activation of human platelets via S1P4 receptor. Thromb. Res. 156, 91-100.   DOI
4 Oskeritzian, C. A., Price, M. M., Hait, N. C., Kapitonov, D., Falanga, Y. T., Morales, J. K., Ryan, J. J., Milstien, S. and Spiegel, S. (2010) Essential roles of sphingosine-1-phosphate receptor 2 in human mast cell activation, anaphylaxis, and pulmonary edema S1P2 axis in anaphylaxis and pulmonary edema. J. Exp. Med. 207, 465-474.   DOI
5 Park, S. J. and Im, D. S. (2017) Sphingosine 1-phosphate receptor modulators and drug discovery. Biomol. Ther. (Seoul) 25, 80-90.   DOI
6 Prussin, C. and Metcalfe, D. D. (2003) 4. IgE, mast cells, basophils, and eosinophils. J. Allergy Clin. Immunol. 111, S486-S494.   DOI
7 Roviezzo, F., Di Lorenzo, A., Bucci, M., Brancaleone, V., Vellecco, V., De Nardo, M., Orlotti, D., De Palma, R., Rossi, F., D'Agostino, B. and Cirino, G. (2007) Sphingosine-1-phosphate/sphingosine kinase pathway is involved in mouse airway hyperresponsiveness. Am. J. Respir. Cell Mol. Biol. 36, 757-762.   DOI
8 Schulze, T., Golfier, S., Tabeling, C., Rabel, K., Graler, M. H., Witzenrath, M. and Lipp, M. (2011) Sphingosine-1-phospate receptor 4 (S1P4) deficiency profoundly affects dendritic cell function and TH17-cell differentiation in a murine model. FASEB J. 25, 4024-4036.   DOI
9 Guerrero, M., Urbano, M., Zhao, J., Crisp, M., Chase, P., Hodder, P., Schaeffer, M. T., Brown, S., Rosen, H. and Roberts, E. (2012) Discovery, design and synthesis of novel potent and selective sphingosine-1-phosphate 4 receptor (S1P4-R) agonists. Bioorg. Med. Chem. Lett. 22, 537-542.   DOI
10 Graler, M. H., Bernhardt, G. and Lipp, M. (1998) EDG6, a novel G-protein-coupled receptor related to receptors for bioactive lysophospholipids, is specifically expressed in lymphoid tissue. Genomics 53, 164-169.   DOI
11 Heo, J. Y. and Im, D. S. (2019) Anti-allergic effects of salvianolic acid A and tanshinone IIA from Salvia miltiorrhiza determined using in vivo and in vitro experiments. Int. Immunopharmacol. 67, 69-77.   DOI
12 Huang, J., Su, M., Lee, B. K., Kim, M. J., Jung, J. H. and Im, D. S. (2018) Suppressive effect of 4-hydroxy-2-(4-hydroxyphenethyl) isoindoline-1,3-dione on ovalbumin-induced allergic asthma. Biomol. Ther. (Seoul) 26, 539-545.   DOI
13 Khalaf, K., Paoletti, G., Puggioni, F., Racca, F., De Luca, F., Giorgis, V., Canonica, G. W. and Heffler, E. (2019) Asthma from immune pathogenesis to precision medicine. Semin. Immunol. 46, 101294.   DOI
14 Kim, M. J. and Im, D. S. (2019) Suppressive effects of type I angiotensin receptor antagonists, candesartan and irbesartan on allergic asthma. Eur. J. Pharmacol. 852, 25-33.   DOI
15 Saluja, R., Kumar, A., Jain, M., Goel, S. K. and Jain, A. (2017) Role of sphingosine-1-phosphate in mast cell functions and asthma and its regulation by non-coding RNA. Front. Immunol. 8, 587.   DOI
16 Kulinski, J. M., Proia, R. L., Larson, E. M., Metcalfe, D. D. and Olivera, A. (2018) S1P(4) regulates passive systemic anaphylaxis in mice but is dispensable for canonical IgE-mediated responses in mast cells. Int. J. Mol. Sci. 19, 1279.   DOI
17 Park, S. J. and Im, D. S. (2019) Blockage of sphingosine-1-phosphate receptor 2 attenuates allergic asthma in mice. Br. J. Pharmacol. 176, 938-949.   DOI
18 Romagnani, S. (2002) Cytokines and chemoattractants in allergic inflammation. Mol. Immunol. 38, 881-885.   DOI
19 Lee, B. K., Park, S. J., Nam, S. Y., Kang, S., Hwang, J., Lee, S. J. and Im, D. S. (2018) Anti-allergic effects of sesquiterpene lactones from Saussurea costus (Falc.) Lipsch. determined using in vivo and in vitro experiments. J. Ethnopharmacol. 213, 256-261.   DOI
20 Van Rijt, L. S. and Lambrecht, B. (2005) Dendritic cells in asthma: a function beyond sensitization. Clin. Exp. Allergy 35, 1125-1134.   DOI
21 Worgall, T. S. (2017) Sphingolipids, ORMDL3 and asthma: what is the evidence? Curr. Opin. Clin. Nutr. Metab. Care 20, 99-103.   DOI
22 Dillmann, C., Mora, J., Olesch, C., Brune, B. and Weigert, A. (2015) S1PR4 is required for plasmacytoid dendritic cell differentiation. Biol. Chem. 396, 775-782.   DOI
23 Tagaya, E. and Tamaoki, J. (2007) Mechanisms of airway remodeling in asthma. Allergol. Int. 56, 331-340.   DOI
24 Allende, M. L., Bektas, M., Lee, B. G., Bonifacino, E., Kang, J., Tuymetova, G., Chen, W., Saba, J. D. and Proia, R. L. (2011) Sphingosine-1-phosphate lyase deficiency produces a pro-inflammatory response while impairing neutrophil trafficking. J. Biol. Chem. 286, 7348-7358.   DOI
25 Ammit, A. J., Hastie, A. T., Edsall, L. C., Hoffman, R. K., Amrani, Y., Krymskaya, V. P., Kane, S. A., Peters, S. P., Penn, R. B., Spiegel, S. and Panettieri, R. A., Jr. (2001) Sphingosine 1-phosphate modulates human airway smooth muscle cell functions that promote inflammation and airway remodeling in asthma. FASEB J. 15, 1212-1214.   DOI
26 Brown, J., Wilson, T. and Metcalfe, D. (2008) The mast cell and allergic diseases: role in pathogenesis and implications for therapy. Clin. Exp. Allergy 38, 4-18.   DOI
27 Choi, O. H., Kim, J.-H. and Kinet, J.-P. (1996) Calcium mobilization via sphingosine kinase in signalling by the FcɛRI antigen receptor. Nature 380, 634-636.   DOI
28 Chiba, Y., Suzuki, K., Kurihara, E., Uechi, M., Sakai, H. and Misawa, M. (2010) Sphingosine-1-phosphate aggravates antigen-induced airway inflammation in mice. Open Respir. Med. J. 4, 82-85.   DOI
29 Jolly, P. S., Bektas, M., Olivera, A., Gonzalez-Espinosa, C., Proia, R. L., Rivera, J., Milstien, S. and Spiegel, S. (2004) Transactivation of sphingosine-1-phosphate receptors by FcɛRI triggering is required for normal mast cell degranulation and chemotaxis. J. Exp. Med. 199, 959-970.   DOI
30 Fettel, J., Kuhn, B., Guillen, N. A., Surun, D., Peters, M., Bauer, R., Angioni, C., Geisslinger, G., Schnutgen, F., Meyer Zu Heringdorf, D., Werz, O., Meybohm, P., Zacharowski, K., Steinhilber, D., Roos, J. and Maier, T. J. (2019) Sphingosine-1-phosphate (S1P) induces potent anti-inflammatory effects in vitro and in vivo by S1P receptor 4-mediated suppression of 5-lipoxygenase activity. FASEB J. 33, 1711-1726.   DOI
31 Moffatt, M. F., Kabesch, M., Liang, L., Dixon, A. L., Strachan, D., Heath, S., Depner, M., von Berg, A., Bufe, A. and Rietschel, E. (2007) Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448, 470-473.   DOI
32 Gilfillan, A. M., Peavy, R. D. and Metcalfe, D. D. (2009) Amplification mechanisms for the enhancement of antigen-mediated mast cell activation. Immunol. Res. 43, 15-24.   DOI
33 Dillmann, C., Ringel, C., Ringleb, J., Mora, J., Olesch, C., Fink, A. F., Roberts, E., Brune, B. and Weigert, A. (2016) S1PR4 signaling attenuates ILT 7 internalization to limit IFN-alpha production by human plasmacytoid dendritic cells. J. Immunol. 196, 1579-1590.   DOI