%0 Journal Article 
%A Kretzer, Christian
%A Jordan, Paul Mike
%A Meyer, Katharina Paula Lydia
%A Hoff, Daniel
%A Werner, Markus
%A Hofstetter, Robert Klaus
%A Koeberle, Andreas
%A Cala Peralta, Antonio
%A Viault, Guillaume
%A Seraphin, Denis
%A Richomme, Pascal
%A Helesbeux, Jean-Jacques
%A Stuppner, Hermann
%A Temml, Veronika
%A Schuster, Daniela
%A Werz, Oliver
%T Natural chalcones elicit formation of specialized pro-resolving mediators and related 15-lipoxygenase products in human macrophages
%D 2021
%@ 1873-2968
%U http://hdl.handle.net/10498/33390
%X 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.
%K chalcones
%K 15-lipoxygenase
%K lipid mediators
%K specialized pro-resolving mediators
%K macrophages
%K inflammation resolution
%~ Universidad de Cádiz