Tanshinone IIA suppresses FcεRI-mediated mast cell signaling and anaphylaxis by activation of the Sirt1/LKB1/AMPK pathway
| Autor: | Youn Ju Lee, Yifeng Deng, Dong Young Kim, Fansi Jin, Jung-Ae Kim, Ju Hye Yang, Kun Ho Son, Hyeun Wook Chang, Jae-Hoon Chang, Soon Jin Park, Makoto Murakami, Xian Li |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Context (language use) Protein Serine-Threonine Kinases Biochemistry Salvia miltiorrhiza 03 medical and health sciences AMP-Activated Protein Kinase Kinases Sirtuin 1 medicine Humans Mast Cells skin and connective tissue diseases Protein kinase A Anaphylaxis Pharmacology biology Receptors IgE Chemistry Kinase Adenylate Kinase Degranulation AMPK Mast cell 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Gene Knockdown Techniques Abietanes biology.protein Cancer research Signal Transduction |
| Zdroj: | Biochemical Pharmacology. 152:362-372 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2018.04.015 |
| Popis: | AMP-activated protein kinase (AMPK) and its upstream mediators liver kinase B1 (LKB1) and sirtuin 1 (Sirt1) are generally known as key regulators of metabolism. We have recently reported that the AMPK pathway negatively regulates mast cell activation and anaphylaxis. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza extract that is currently used for the treatment of cardiovascular and cerebrovascular diseases, shows anti-diabetic activity and improves insulin resistance in db/db mice through activation of AMPK. The aim of this study was to evaluate the anti-allergic activity of Tan IIA in vivo and to investigate the underlying mechanism in vitro in the context of AMPK signaling. The anti-allergic effect of Tan IIA was evaluated using mouse bone marrow-derived mast cells (BMMCs) from AMPKα2-/- or Sirt1-/- mice, or BMMCs transfected with siRNAs specific for AMPKα2, LKB1, or Sirt1. AMPKα2-/- and Sirt1-/- mice were used to confirm the anti-allergic effect of Tan IIA in anaphylaxis in vivo. Tan IIA dose-dependently inhibited FceRI-mediated degranulation and production of eicosanoids and cytokines in BMMCs. These inhibitory effects were diminished by siRNA-mediated knockdown or genetic deletion of AMPKα2 or Sirt1. Moreover, Tan IIA inhibited a mast cell-mediated local passive anaphylactic reaction in wild-type mice, but not in AMPKα2-/- or Sirt1-/- mice. In conclusion, Tan IIA suppresses FceRI-mediated mast cell activation and anaphylaxis through activation of the inhibitory Sirt1-LKB1-AMPK pathway. Thus, Tan IIA may be useful as a new therapeutic agent for mast cell-mediated allergic diseases. |
| Databáze: | OpenAIRE |
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