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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059638-04
Application #
7755015
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dong, Gang
Project Start
2007-02-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$358,341
Indirect Cost
Name
Virginia Commonwealth University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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
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
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
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
Oskeritzian, Carole A; Hait, Nitai C; Wedman, Piper et al. (2015) The sphingosine-1-phosphate/sphingosine-1-phosphate receptor 2 axis regulates early airway T-cell infiltration in murine mast cell-dependent acute allergic responses. J Allergy Clin Immunol 135:1008-18.e1
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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