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Article Dans Une Revue Biochemical Pharmacology Année : 2022

Natural chalcones elicit formation of specialized pro-resolving mediators and related 15-lipoxygenase products in human macrophages

Christian Kretzer
  • Fonction : Auteur
Paul Jordan
  • Fonction : Auteur
Katharina P.L. Meyer
  • Fonction : Auteur
Daniel Hoff
Markus Werner
  • Fonction : Auteur
Robert Klaus Hofstetter
  • Fonction : Auteur
Andreas Koeberle
Hermann Stuppner
Veronika Temml
Daniela Schuster
Oliver Werz

Résumé

Specialized pro-resolving mediators (SPMs) comprise lipid mediators (LMs) produced from polyunsaturated fatty acids (PUFAs) via stereoselective oxygenation particularly involving 12/15-lipoxygenases (LOXs). In contrast to pro-inflammatory LMs such as leukotrienes formed by 5-LOX and prostaglandins formed by cyclooxygenases, the SPMs have anti-inflammatory and inflammation-resolving properties. Although glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) that block prostaglandin production are still prime therapeutics for inflammation-related diseases despite severe side effects, novel concepts focus on SPMs as immunoresolvents for anti-inflammatory pharmacotherapy. Here, we studied the natural chalcone MF-14 and the corresponding dihydrochalcone MF-15 from Melodorum fruticosum, for modulating the biosynthesis of LM including leukotrienes, prostaglandins, SPM and their 12/15-LOX-derived precursors in human monocyte-derived macrophage (MDM) M1- and M2-like phenotypes. In MDM challenged with Staphylococcus aureus-derived exotoxins both compounds (10 µM) significantly suppressed 5-LOX product formation but increased the biosynthesis of 12/15-LOX products, especially in M2-MDM. Intriguingly, in resting M2-MDM, MF-14 and MF-15 strikingly evoked generation of 12/15-LOX products and of SPMs from liberated PUFAs, along with translocation of 15-LOX-1 to membranous compartments. Enhanced 12/15-LOX product formation by the chalcones was evident also when exogenous PUFAs were supplied, excluding increased substrate supply as sole underlying mechanism. Rather, MF-14 and MF-15 stimulate the activity of 15-LOX-1, supported by experiments with HEK293 cells transfected with either 5-LOX, 15-LOX-1 or 15-LOX-2. Together, the natural chalcone MF-14 and the dihydrochalcone MF-15 favorably modulate LM biosynthesis in human macrophages by suppressing pro-inflammatory leukotrienes but stimulating formation of SPMs by differential interference with 5-LOX and 15-LOX-1.
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Dates et versions

hal-03533844 , version 1 (22-09-2023)

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Citer

Christian Kretzer, Paul Jordan, Katharina P.L. Meyer, Daniel Hoff, Markus Werner, et al.. Natural chalcones elicit formation of specialized pro-resolving mediators and related 15-lipoxygenase products in human macrophages. Biochemical Pharmacology, 2022, 195, pp.114825. ⟨10.1016/j.bcp.2021.114825⟩. ⟨hal-03533844⟩

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