Thymoquinone strongly inhibits fMLF-induced neutrophil functions and exhibits anti-inflammatory properties in vivo

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• 作者：Kaouthar Boudiaf^a ; ^b ; ^c ; ^d ; Margarita Hurtado-Nedelec^a ; ^b ; Sahra Amel Belambri^a ; ^b ; Jean-Claude Marie^a ; ^b ; Yacine Derradji^e ; Mustapha Benboubetra^d ; Jamel El-Benna^a ; ^b ; Pham My-Chan Dang^a ; ^b ; ^{my-chan.dang@inserm.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AIR ; auto-inhibitory region ; DFP ; Diisopropyl fluorophosphate ; ECL ; enhanced chemiluminescence ; ERK ; extracellular signal-regulated kinase ; fMLF ; N-formyl-methionyl-leucyl-phenylalanine ; HBSS ; Hank&rsquo ; s balanced salt solution ; IBD ; inflammatory bowel disease ; MAPK ; mitogen-activated protein kinase ; MPO ; myeloperoxidase ; NOX ; neutrophil oxidase ; PKC ; Protein Kinase C ; PMA ; phorbol myristate acetate ; PMN ; polymorphonuclear neutrophil ; RA ; rheumatoid arthritis ; ROS ; reactive oxygen species ; SH3
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：104
• 期：Complete
• 页码：62-73
• 全文大小：1049 K

文摘

Polymorphonuclear neutrophils are key players in host defense against pathogens through the robust production of superoxide anion by the NADPH oxidase and the release of antibacterial proteins from granules. However, inappropriate release of these agents in the extracellular environment induces severe tissue injury, thereby contributing to the physiopathology of acute and chronic inflammatory disorders. Many studies have been carried out to identify molecules capable of inhibiting phagocyte functions, in particular superoxide anion production, for therapeutic purposes. In the present study, we show that thymoquinone (TQ), the major component of the volatile oil from Nigella sativa (black cumin) seeds strongly inhibits fMLF-induced superoxide production and granules exocytosis in neutrophils. The inhibition of superoxide anion was not due to a scavenger effect, as TQ did not inhibit superoxide anion produced by the xanthine/xanthine oxidase system. Interestingly, TQ impaired the phosphorylation on Ser-304 and Ser-328 of p47^PHOX, a cytosolic subunit of the NADPH oxidase. TQ also attenuated specific and azurophilic granule exocytosis in fMLF-stimulated neutrophils as evidenced by decreased cell surface expression of gp91^PHOX and CD11b, and release of myeloperoxidase. Furthermore, both the PKC and MAPK pathways, which are involved in p47^PHOX phosphorylation and granules exocytosis, respectively, were inhibited by TQ in fMLF-stimulated neutrophils. Finally, in a model of pleurisy induced by λ-carrageenan in rats, TQ reduced neutrophil accumulation in the pleural space, showing that it not only inhibits PMN functions in vitro, but also exhibits anti-inflammatory properties in vivo. Thus, TQ possesses promising anti-inflammatory therapeutic potential.