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Article in English | WPRIM | ID: wpr-186263


Previously, we reported that CD40-induced production of reactive oxygen species (ROS) by NADPH oxidase requires the TNF receptor-associated factor (TRAF) 3, as well as the activities of phosphatidylinositol 3-kinase (PI3K) and Rac1. Here we investigated the possible mechanisms of the production of ROS after CD40 ligation in B cells. We describe an alternative ROS production pathway that is triggered by CD40 ligation, involves 5-lipoxygenase (5-LO), and results in activation of p38 MAPK. Our studies in Raji human B lymphomas revealed that CD40-induced ROS production by 5-LO also requires the activities of PI3K and Rac1. In contrast to the NADPH oxidase pathway, however, TRAF molecules are not required for the CD40-induced ROS production by 5-LO. The association of CD40 with 5-LO is dependent on CD40 ligation in Raji B cells, and co-immunoprecipitation experiments using epitope-tagged proteins transiently expressed in human embryonic kidney 293T cells revealed the role of the regulatory subunit of PI3K, p85, in this association. Collectively, these data suggest a separate pathway for the CD40-induced ROS production in B cells and demonstrate that this pathway requires 5-LO via direct association of p85 with both CD40 and 5-LO.

CD40 Antigens/metabolism , Arachidonate 5-Lipoxygenase/metabolism , B-Lymphocytes/enzymology , CD40 Ligand/metabolism , Cell Line, Tumor , Enzyme Activation , HEK293 Cells , Humans , Phosphatidylinositol 3-Kinases/metabolism , Protein Binding , Reactive Oxygen Species/metabolism , Signal Transduction , p38 Mitogen-Activated Protein Kinases/metabolism , rac GTP-Binding Proteins/metabolism