Mast cells reside at the host-environment interface, serving as immune sentinels in both protective and pathological responses. The high affinity IgE receptor, Fc?RI, is the best-understood mast cell-activating pathway. Mast cell homeostasis is likely regulated by cytokines produced in the inflammatory response, perhaps in an autocrine fashion. We demonstrate that IL-10 suppresses Fc?RI-mediated activation by targeting Fyn, Stat5, and Akt for degradation. Importantly, this suppression is observed in mast cells from Th1-prone C57BL/6 but not Th2-prone BALB/c or 129/Sv mice. IL-10 sensitivity correlates with the induction of microRNAs (miRs) potentially targeting Fyn, Stat5B, and Akt. While Fyn is known to activate Akt, the role of Stat5 is less understood. We find that Stat5B is critical for Fc?RI-induced cytokine production. We demonstrate that Stat5 tyrosine phosphorylation is Fyn-dependent and that Fyn physically interacts with Stat5. Stat5 is also serine phosphorylated during IgE signaling, through a Fyn-independent pathway. We will determine how the Fyn-Stat5/Akt pathway is regulated by IL-10, and if resistance to this suppression correlates with allergic disease. Our hypothesis is that Fc?RI activation is limited by feedback signaling via IL-10-induced miRs that selectively dampen the Fyn-Stat5/Akt pathway. Loss of this regulation in a non-permissive genetic background could be part of atopic etiology.
Specific Aims I. To test the hypothesis that IL-10 antagonizes the Fyn-Stat5/Akt pathway via genotype-restricted effects on miR induction in mast cells and basophils. II. To test the hypothesis that Stat5B is critical for Fc?RI signaling in mast cells and basophils. III. To test the hypothesis that IL-10 suppresses Fc?RI responses in vivo by antagonizing the Fyn-Stat5/Akt pathway.

Public Health Relevance

Chronic mast cell activation is at the center of allergic diseases like asthma. We have uncovered mast cell suppression by IL-10, which appears to be deficient in mice, and perhaps people, with a genetic predisposition to allergic disease. Our study will test the hypothesis that IL-10 is a natural feedback regulator of mast cell-mediated inflammation, and that loss of this process contributes to allergic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI059638-06A1
Application #
8577549
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dong, Gang
Project Start
2004-03-01
Project End
2018-05-31
Budget Start
2013-06-15
Budget End
2014-05-31
Support Year
6
Fiscal Year
2013
Total Cost
$353,248
Indirect Cost
$118,248
Name
Virginia Commonwealth University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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