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Zymosan induces NADPH oxidase activation in human neutrophils by inducing the phosphorylation of p47phox and the activation of Rac2: Involvement of protein tyrosine kinases,PI3Kinase,PKC, ERK1/2 and p38MAPkinase
Authors:Karama Makni-Maalej  Mélanie Chiandotto  Margarita Hurtado-Nedelec  Samia Bedouhene  Marie-Anne Gougerot-Pocidalo  Pham My-Chan Dang  Jamel El-Benna
Affiliation:1. INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Paris F-75018, France;2. Université Paris 7 site Bichat, UMRS 773, Paris F-75018, France;3. AP-HP, Centre Hospitalier Universitaire Xavier Bichat, UF Dysfonctionnements Immunitaires, Paris F-75018, France
Abstract:Reactive oxygen species (ROS) production by the neutrophil NADPH oxidase plays a key role in host defense against pathogens, such as bacteria and fungi. Zymosan a cell-wall preparation from Saccharomyces cerevisiae is largely used to activate neutrophils in its opsonized form. In this study, we show that non-opsonized zymosan alone induced ROS production by human neutrophils. Zymosan-induced ROS production is higher than the formyl-methionyl-leucyl-phenylalanine (fMLF)- or the phorbol myristate acetate (PMA)-induced ROS production but is lower than the one induced by opsonized zymosan. Most of the zymosan-induced ROS production is intracellular. Interestingly, zymosan induced the phosphorylation of the NADPH oxidase cytosolic component p47phox on several sites which are Ser315, Ser328 and Ser345. Zymosan induced also the activation of the small G-protein Rac2. Phosphorylation of the p47phox as well as Rac2 activation were inhibited by genistein a broad range protein tyrosine kinase inhibitor and by wortmannin a PI3Kinase inhibitor. GF109203X a PKC inhibitor inhibited phosphorylation of p47phox on Ser315 and Ser328. SB203580 and UO126, inhibitors of p38MAPK and ERK1/2-pathway, respectively, inhibited phosphorylation of p47phox on Ser345. Zymosan-induced ROS production was completely inhibited by genistein and wortmannin and partially inhibited by SB203580, UO126 and GF109203X. These results show that zymosan alone is able to activate NADPH oxidase in human neutrophils via the phosphorylation of p47phox and Rac2 activation and that a protein tyrosine kinase, PI3Kinase, p38MAPK, ERK1/2 and PKC are involved in this process. These pathways could be potential pharmacological targets to treat zymosan- and S. cerevisiae-induced inflammation.
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