Our proposal will investigate the clinically important area of mast cell homeostasis. Mast cells are well-known for their role in allergy and asthma, and have recently been implicated in inflammatory disorders such as multiple sclerosis, arthritis, and heart disease. A critical gap in the understanding of inflammatory disease is how the mast cell response is normally dampened to prevent chronic inflammation. Our hypothesis is that IL-10 is an endogenous mediator of mast cell homeostasis. We present clear evidence that IL-10 suppresses the function and survival of mouse and human mast cells. Preliminary in vivo studies corroborate these data. We also show that IL-10 may be provided by two sources: (I) autocrine production from activated mast cells, and (II) paracrine production from CD25+ regulatory T cells (Treg). Manipulating mast cell homeostasis could be a powerful tool for the treatment of inflammatory disease.
Our Specific Aims are: I. To determine how IL-10 suppresses IgE receptor expression and function in vitro and in vivo. We will test the following hypotheses: A. IL-10 employs Stat5 to inhibit Fc?RI function, by suppressing Syk, Akt, and Stat5 expression. B. IL-10 suppresses Fc?RI expression in vivo, and mitigates IgE-mediated anaphylaxis. C. IL-10 is provided by activated mast cells and by recruited Tregs. D. Tregs suppress mast cell function in vivo by producing IL-10. II. To determine how IL-10 inhibits mast cell proliferation and survival in vitro and in vivo. We will test the following hypotheses: A. IL-10 induces cell cycle arrest and apoptosis in mast cells by inhibiting Stat5 and Akt expression. B. Tregs inhibit mast cell proliferation and survival by secreting IL-10. C. IL-10, possibly derived from Tregs, suppresses mast cell hyperplasia in vivo. ? ? ? ?
| Caslin, Heather L; Taruselli, Marcela T; Paranjape, Anuya et al. (2018) The Use of Human and Mouse Mast Cell and Basophil Cultures to Assess Type 2 Inflammation. Methods Mol Biol 1799:81-92 |
| McLeod, Jamie Josephine Avila; Caslin, Heather L; Spence, Andrew J et al. (2017) Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IgE-mediated mast cell activation through attenuation of NF?B and AP-1 transcription. Cell Immunol 322:41-48 |
| Caslin, Heather L; McLeod, Jamie Josephine Avila; Spence, Andrew J et al. (2017) Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IL-33-induced cytokine production in primary mouse mast cells. Cell Immunol 319:10-16 |
| Ndaw, Victor S; Abebayehu, Daniel; Spence, Andrew J et al. (2017) TGF-?1 Suppresses IL-33-Induced Mast Cell Function. J Immunol 199:866-873 |
| Abebayehu, Daniel; Spence, Andrew; Boyan, Barbara D et al. (2017) Galectin-1 promotes an M2 macrophage response to polydioxanone scaffolds. J Biomed Mater Res A 105:2562-2571 |
| Kolawole, Elizabeth Motunrayo; McLeod, Jamie Josephine Avila; Ndaw, Victor et al. (2016) Fluvastatin Suppresses Mast Cell and Basophil IgE Responses: Genotype-Dependent Effects. J Immunol 196:1461-70 |
| Paranjape, Anuya; Chernushevich, Oksana; Qayum, Amina Abdul et al. (2016) Dexamethasone rapidly suppresses IL-33-stimulated mast cell function by blocking transcription factor activity. J Leukoc Biol 100:1395-1404 |
| Abebayehu, Daniel; Spence, Andrew J; Qayum, Amina Abdul et al. (2016) Lactic Acid Suppresses IL-33-Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1?-Dependent miR-155 Suppression. J Immunol 197:2909-17 |
| Qayum, Amina Abdul; Paranjape, Anuya; Abebayehu, Daniel et al. (2016) IL-10-Induced miR-155 Targets SOCS1 To Enhance IgE-Mediated Mast Cell Function. J Immunol 196:4457-67 |
| McLeod, Jamie J A; Baker, Bianca; Ryan, John J (2015) Mast cell production and response to IL-4 and IL-13. Cytokine 75:57-61 |
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