LEUKOTRIENE B4 STIMULATES RAC-ERK CASCADE TO GENERATE REACTIVE OXYGEN SPECIES THAT MEDIATES CHEMOTAXIS

다국어 초록 (Multilingual Abstract)

Leukotriene B₄ is a potent chemoattractant that is mainly involved in inflammation, immune responses and host defense against infection. Despite the well-known roles of leukotriene B₄ in inflammatory reactions, the exact signaling mechanisms by which leukotriene B₄ exerts its effects in the cells are not well characterized yet, especially the event leading to ROS generation. Here, we report that exogenous leukotriene B₄ induces ROS generation via a Rac-dependent pathway based on the observation that stable expression of Rac^(N17), a dominant negative Rac1 mutant, completely blocked leukotriene B₄-induced ROS generation. In addition, Leukotriene B₄-induced ROS generation was selectively blocked by inhibition of ERK or cytosolic phospholipase A₂, but not p38 kinase, suggesting that leukotriene B₄-induced ROS generation is dependent on ERK activation and synthesis of arachidonic acid. Consistent with that prediction, leukotriene B₄ Rac-dependently stimulated ERK or cytosolic phospholipase A₂ activity, while transient transfection with plasmid expressing Rac^(V12), a constitutively activated Rac1 mutant, stimulates ERK activity in a dose-dependent manner. Our findings suggest that ERK and cytosolic phospholipase A₂ are situated downstream of Rac, and we conclude that Rac, ERK, and cytosolic phospholipase A₂ play pivotal roles mediating the ROS generation triggered by leukotriene B₄. Importantly, the ROS generation by leukotriene B₄ appears to be prerequisite for the leukotriene B₄-induced chemotaxis as well as proliferation.