Anti-inflammatory celastrol promotes a switch from leukotriene biosynthesis to formation of specialized pro-resolving lipid mediators
| Autor: | Paul M. Jordan, Oliver Werz, Christian Kretzer, Kehong Zhang, Friedemann Börner, Dagmar Fischer, Robert K. Hofstetter, Xinchun Chen, Marianna Potenza, Wenfei Wang, Simona Pace, Nathaniel C. Gilbert, Jana Gerstmeier, Antonietta Rossi, Rossella Bilancia, Marcia E. Newcomer, Stefan Lorkowski |
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| Přispěvatelé: | Pace, S., Zhang, K., Jordan, P. M., Bilancia, R., Wang, W., Borner, F., Hofstetter, R. K., Potenza, M., Kretzer, C., Gerstmeier, J., Fischer, D., Lorkowski, S., Gilbert, N. C., Newcomer, M. E., Rossi, A., Chen, X., Werz, O. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Anti-Inflammatory Agents Mice chemistry.chemical_compound 0302 clinical medicine celastrol (PubChem CID: 122724) Lipoxygenase Inhibitors Cells Cultured Leukotriene biology indomethacin (PubChem CID: 3715) Celastrol Cell biology Molecular Docking Simulation 030220 oncology & carcinogenesis Arachidonate 5-lipoxygenase 5-lipoxygenase resolvin D5 (PubChem CID: 16061139) dimethyl sulfoxide (PubChem CID: 679) medicine.symptom zileuton (PubChem CID: 60490) Pentacyclic Triterpenes Resolvin Leukotrienes Tripterygium medicine.drug_class Inflammation MK886 (PubChem CID: 3651377) Anti-inflammatory 03 medical and health sciences In vivo zymosan (PubChem CID: 64689) medicine Animals Humans arachidonic acid (PubChem CID: 444899) Pharmacology Arachidonate 5-Lipoxygenase Specialized pro-resolving mediator Lipid signaling Lipid Metabolism Biosynthetic Pathways 030104 developmental biology chemistry biology.protein celecoxib (PubChem CID: 2662) |
| Popis: | 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 IC50 = 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. |
| Databáze: | OpenAIRE |
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