Journal
INTERNATIONAL IMMUNOPHARMACOLOGY
Volume 71, Issue -, Pages 22-31Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.intimp.2019.03.013
Keywords
Isosalvianolic acid C; Mast cell; MRGPRX2; MrgprB2; Pseudo-allergic
Categories
Funding
- National Natural Science Foundation of China [81503032, 81230079, 81227802]
- National China Postdoctoral Science Foundation [2015M570844, 2016T90930]
- Natural Science Foundation of Shaanxi Province [2017JM8050]
- Shaanxi Province Postdoctoral Science Foundation
- Fundamental Research Funds for the Central Universities
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Pseudo-allergic reactions occurred in patients administered drugs for the first time, seriously threaten man's survival. Due to the frequent reports of pseudo-allergic reactions to Danshen injection, in our previous study, isosalvianolic acid C in Danshen injection was found to trigger off mast cell degranulation. However, the direct involvement and the mechanisms underlying pseudo-allergic reactions have not been elucidated. In this study, the pseudo-allergic reactions induced by isosalvianolic acid C were confirmed by an ear swelling assay, a hindpaw swelling and extravasation assay in vivo and mast cell degranulation assays in vitro. We also evaluated whether the pseudo-allergic effect is related to MRGPRX2, Isosalvianolic acid C induced Ca2+ mobilization was verified as MRGPRX2-related by Ca2+ imaging using mouse peritoneal mast cells (both wild-type and MrgprB2 knockout mice), MRGPRX2-expressing HEK293 and MrgprB2-expressing HEK293 cells. MRGPRX2-related pseudo-allergic reactions induced by Isosalvianolic acid C were further confirmed by MrgprB2 knockout mice and MRGPRX2 knockdown mast cells both exhibited reduced isosalvianolic acid C-induced pseudo-allergic effects. Furthermore, both the frontal analysis and molecular docking assays showed that isosalvianolic acid C has a considerable affinity with MRGPRX2. Based on the above experiments, the western blot analyses were conducted, the results indicated that isosalvianolic acid C induced Ca2+ mobilization and degranulation via the activation of PLC-gamma and IP3R, and releasing chemokines via the activation of PLC-gamma, PKC and P38. This study should alarm many clinicians that medicines containing isosalvianolic acid C might induce pseudo-allergic reactions, and it may provide guidance on safe dosage of these medicines in the process of production and use.
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