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    Contributions of mitogen-activated protein kinase signaling on mast cell differentiation and allergic phenotype

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    Author
    Hicks, Natalie
    Keyword
    mast cells
    MAPK pathway
    JNK
    ERK
    p38
    
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    URI
    http://hdl.handle.net/10464/15136
    Abstract
    Introduction: Mast cells are large granulated immune cells, and major drivers of allergic inflammation. Increased inflammatory activity and numbers of mast cells contribute to allergic disease, which is of increasing concern worldwide. Mast cells are derived from hematopoietic stem cells, which are found in the bone marrow. Specifics regarding the molecular mechanisms that control mast cell differentiation remain largely undiscovered. The mitogen activated protein kinase (MAPK) pathway is a highly evolutionarily conserved intracellular signaling pathway that is active in all eukaryotic cells. We sought to evaluate the role of the three major nodes of the MAPK pathway—JNK, ERK, and p38—in IL-3-mediated mast cell differentiation. Methods: Bone marrow-derived mast cell (BMMC) cultures were initiated from the bone marrow of C57BL/6 mice and differentiated in the presence of MAPK inhibitors. One group received 1 µM of JNK inhibitor JNK-IN-8, another 1 µM of the ERK inhibitor SCH772984, another 10 µM of the p38 inhibitor Losmapimod. The control group received no inhibitor. The β-hexosaminidase release assay was used to assess mast cell degranulation; enzyme-linked immunosorbent assay (ELISA) was used to measure cytokine secretion; and flow cytometry was used to measure marker and receptor expression. Results: In the JNK group, cells exhibited a reduced capability to degranulate, a down-regulation in IL-13, CCL1, CCL2, and an up-regulation in basal CCL9 secretion. In the ERK group, mast cells secreted decreased amounts of CCL2, increased amounts of CCL3, and down-regulated c-kit expression on the cell surface. In the p38 group, mast cells exhibited an increased capability to degranulate, secreted lower amounts of CCL1 and CCL2, and exhibited increased c-kit expression on the cell surface. Conclusion: Overall, JNK inhibition negatively affects both the early and late phases of allergic inflammation, ultimately producing an impaired inflammatory phenotype. ERK inhibition affects the late phase of allergic inflammation and cell surface receptor expression. p38 inhibition affects both the early and late phases of allergic inflammation, as well as cell surface receptor expression. This research contributes to the fundamental biological understanding of mast cell differentiation and may drive the development of future therapeutics for allergic disease.
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