BLT2 Is upregulated in allergen-stimulated mast cells and mediates the synthesis of Th2 cytokines.
Mast cells are effector cells that mediate the allergic response through Ag stimulation of IgE bound to FcεRI. In allergic reactions, cross-linking of the surface receptors for IgE on mast cells results in the synthesis of Th2 cytokines such as IL-4 and IL-13, which are critical for the initiation and progression of the allergic response. Despite the important roles of these cytokines, the signaling mechanism by which Ag stimulation mediates the production of IL-4 and IL-13 in mast cells is not clearly understood. In the present study, we found that Ag-stimulated bone marrow-derived mast cells (BMMCs) highly upregulated the expression of BLT2, a leukotriene B(4) receptor, and that blockade of BLT2 with the specific antagonist LY255283 or small interfering RNA knockdown completely abolished the production of Th2 cytokines. Furthermore, BMMCs overexpressing BLT2 showed significantly enhanced production of Th2 cytokines compared with wild-type BMMCs. Additionally, we found that the generation of Nox1-derived reactive oxygen species occurs downstream of BLT2, thus mediating the synthesis of Th2 cytokines. Taken together, our results suggest that the BLT2-Nox1-reactive oxygen species cascade is a previously unsuspected mediatory signaling mechanism to Th2 cytokine production in Ag-stimulated BMMCs, thus contributing to allergic response.
Cho
Kyung-Jin
KJ
College of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
Seo
Ji-Min
JM
Lee
Min-Goo
MG
Kim
Jae-Hong
JH
D000485:Allergens / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism; D007377:Interleukin-3 / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009247:NADH, NADPH Oxidoreductases / Q000276:immunology / Q000378:metabolism; D000074624:NADPH Oxidase 1; D034622:RNA Interference; D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4 / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation
D000485:Allergens; D016207:Cytokines; D007377:Interleukin-3; C412867:Ltb4r2 protein, mouse; D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4; D015847:Interleukin-4; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse