Histamine synthesis is required for granule maturation in murine mast cells |
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| Authors: | Kazuyuki Furuta Mayuko Natsuhara Hirotsugu Takano Soken Tsuchiya Yasushi Okuno Hiroshi Ohtsu Masahiro Nishibori Robin L. Thurmond Noriyasu Hirasawa Kazuhisa Nakayama Atsushi Ichikawa Yukihiko Sugimoto Satoshi Tanaka |
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| Affiliation: | 1. Department of Immunobiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;2. Department of Immunobiology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo, Japan;3. Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan;4. Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan;5. Department of Systems Bioscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan;6. Laboratory of Applied Quantum Medical Engineering, Graduate School of Engineering, Tohoku University, Sendai, Japan;7. Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;8. Janssen Research & Development, LLC, San Diego, CA, USA;9. Laboratory of Pharmacotherapy, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan;10. Institute for Biosciences, Mukogawa Women's University, Nishinomiya, Hyogo, Japan |
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| Abstract: | Mast cells are the major sources of histamine, which is released in response to immunological stimulations. The synthesis of histamine is catalyzed by histidine decarboxylase (HDC). Previous studies have shown that Hdc?/? mast cells exhibit aberrant granule morphology with severely decreased granule content. Here, we investigated whether the histamine synthesized in mast cells regulates the granule maturation of murine mast cells. Several genes, including those encoding granule proteases and enzymes involved in heparin biosynthesis, were downregulated in Hdc?/? peritoneal mast cells. Impaired granule maturation was also found in Hdc?/? BM‐derived cultured mast cells when they were cocultured with fibroblasts in the presence of c‐kit ligand. Exogenous application of histamine and several H4 receptor agonists restored the granule maturation of Hdc?/? cultured mast cells. However, the maturation of granules was largely normal in Hrh4?/? peritoneal mast cells. Depletion of cellular histamine with tetrabenazine, an inhibitor of vesicular monoamine transporter‐2, did not affect granule maturation. In vivo experiments with mast cell deficient KitW/KitW‐v mice indicated that the expression of the Hdc gene in mast cells is required for granule maturation. These results suggest that histamine promotes granule maturation in mast cells and acts as an proinflammatory mediator. |
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| Keywords: | Cell differentiation Histamine Inflammation Mast cell |
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