Anti-inflammatory celastrol promotes a switch from leukotriene biosynthesis to formation of specialized pro-resolving lipid mediators. (May 2021)

• Record Type: Journal Article
• Authors: Pace, Simona; Zhang, Kehong; Jordan, Paul M.; Bilancia, Rossella; Wang, Wenfei; Börner, Friedemann; Hofstetter, Robert K.; Potenza, Marianna; Kretzer, Christian; Gerstmeier, Jana; Fischer, Dagmar; Lorkowski, Stefan; Gilbert, Nathaniel C.; Newcomer, Marcia E.; Rossi, Antonietta; Chen, Xinchun; Werz, Oliver
• Is Part Of: Pharmacological research. Volume 167(2021)
• Publication Date: 2021-05
• Subjects: AA arachidonic acid -- 5-HpETE 5-hydro(pero)xy-eicosatetraenoic acid -- 12-HHT 12(S)-hydroxy-5-cis-8, 10-trans-heptadecatrienoic acid -- COX cyclooxygenase -- DHA docosahexaenoic acid -- EPA eicosapentaenoic acid -- FCS fetal calf serum -- IFN interferon -- IL interleukin -- LM lipid mediator -- LOX lipoxygenase -- LPS lipopolysaccharide -- LT leukotriene -- mPGES-1 microsomal prostaglandin E2 synthase 1 -- MDM monocyte-derived macrophages -- PBMC peripheral blood mononuclear cells -- PG prostaglandin -- PMNL polymorphonuclear leukocytes -- RP reversed phase -- SACM Staphylococcus aureus-conditioned medium -- SPE solid phase extraction -- SPM specialized pro-resolving mediator -- TwHF Tripterygium wilfordii Hook. F. -- TX thromboxane -- TXAS thromboxane A synthase -- UPLC-MS-MS ultra-performance liquid chromatography coupled to tandem mass spectrometry; arachidonic acid (PubChem CID: 444899) -- celastrol (PubChem CID: 122724) -- celecoxib (PubChem CID: 2662) -- dimethyl sulfoxide (PubChem CID: 679) -- indomethacin (PubChem CID: 3715) -- MK886 (PubChem CID: 3651377) -- resolvin D5 (PubChem CID: 16061139) -- zileuton (PubChem CID: 60490) -- zymosan (PubChem CID: 64689); Celastrol -- Specialized pro-resolving mediators -- 5-lipoxygenase -- Leukotriene -- Inflammation; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.105556
• Languages: English
• ISSNs: 1043-6618

Abstract

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 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. Graphical Abstract: ga1 Highlights: 5-LOX is a high affinity target for celastrol (CS) with IC50 of 0.19–0.49 µM. CS blocks 5-LOX-derived leukotriene formation in PMNL and M1 macrophages. in M2 macrophages CS elicits specialized pro-resolving mediator (SPM) formation. CS impairs the levels of leukotrienes but elevates SPM in murine peritonitis.