Title

Anti-inflammatory celastrol promotes a switch from leukotriene biosynthesis to formation of specialized pro-resolving lipid mediators

Authors

Simona Pace, Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: simona.pace@uni-jena.de.
Kehong Zhang, Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany; Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen 518000, China. Electronic address: kehong.zhang@uni-jena.de.
Paul M. Jordan, Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: paul.jordan@uni-jena.de.
Rossella Bilancia, Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via D. Montesano 49, I-80131 Naples, Italy. Electronic address: rossella.bilancia@unina.it.
Wenfei Wang, Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany; Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen 518000, China. Electronic address: wenfei.wang@uni-jena.de.
Friedemann Börner, Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany.
Robert K. Hofstetter, Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: robert.klaus.hofstetter@uni-jena.de.
Marianna Potenza, Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, I-84084 Fisciano, Italy. Electronic address: mpontenza@unisa.it.
Christian Kretzer, Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: Christian.kretzer@uni-jena.de.
Jana Gerstmeier, Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: jana.gerstmeier@uni-jena.de.
Dagmar Fischer, Department of Chemistry and Pharmacy, Pharmaceutical Technology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Cauerstrasse 4, 91058 Erlangen, Germany. Electronic address: dagmar.fischer@fau.de.
Stefan Lorkowski, Department of Nutritional Biochemistry and Physiology, Institute of Nutritional Sciences, Friedrich Schiller University, Dornburger Str. 25, 07743 Jena, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Germany. Electronic address: stefan.lorkowski@uni-jena.de.
Nathaniel C. Gilbert, Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, USA. Electronic address: ngilbert@lsu.edu.
Marcia E. Newcomer, Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, USA. Electronic address: newcomer@lsu.edu.
Antonietta Rossi, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via D. Montesano 49, I-80131 Naples, Italy. Electronic address: antrossi@unina.it.
Xinchun Chen, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen 518000, China. Electronic address: chenxinchun@szu.edu.cn.
Oliver Werz, Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.

Document Type

Article

Publication Date

5-1-2021

Abstract

The pentacyclic triterpenoid quinone methide celastrol (CS) from Tripterygium wilfordii Hook. F. effectively ameliorates inflammation with potential as therapeutics for inflammatory diseases. However, the molecular mechanisms underlying the anti-inflammatory and inflammation-resolving features of CS are incompletely understood. Here we demonstrate that CS potently inhibits the activity of human 5-lipoxygenase (5-LOX), the key enzyme in pro-inflammatory leukotriene (LT) formation, in cell-free assays with IC = 0.19-0.49 µM. Employing metabololipidomics using ultra-performance liquid chromatography coupled to tandem mass spectrometry in activated human polymorphonuclear leukocytes or M1 macrophages we found that CS (1 µM) potently suppresses 5-LOX-derived products without impairing the formation of lipid mediators (LM) formed by 12-/15-LOXs as well as fatty acid substrate release. Intriguingly, CS induced the generation of 12-/15-LOX-derived LM including the specialized pro-resolving mediator (SPM) resolvin D5 in human M2 macrophages. Finally, intraperitoneal pre-treatment of mice with 10 mg/kg CS strongly impaired zymosan-induced LT formation and simultaneously elevated the levels of SPM and related 12-/15-LOX-derived LM in peritoneal exudates, spleen and plasma in vivo. Conclusively, CS promotes a switch from LT biosynthesis to formation of SPM which may underlie the anti-inflammatory and inflammation-resolving effects of CS, representing an interesting pharmacological strategy for intervention with inflammatory disorders.

Publication Source (Journal or Book title)

Pharmacological research

First Page

105556

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