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.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation (III)
Program Officer
Dong, Gang
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
Schools of Arts and Sciences
United States
Zip Code
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
Martin, Rebecca K; Saleem, Sheinei J; Folgosa, Lauren et al. (2014) Mast cell histamine promotes the immunoregulatory activity of myeloid-derived suppressor cells. J Leukoc Biol 96:151-9
Morales, Johanna K; Saleem, Sheinei J; Martin, Rebecca K et al. (2014) Myeloid-derived suppressor cells enhance IgE-mediated mast cell responses. J Leukoc Biol 95:643-50
Mangrum, John B; Engelmann, Brigitte J; Peterson, Erica J et al. (2014) A new approach to glycan targeting: enzyme inhibition by oligosaccharide metalloshielding. Chem Commun (Camb) 50:4056-8
Faber, Travis W; Pullen, Nicholas A; Fernando, Josephine F A et al. (2014) ADAM10 is required for SCF-induced mast cell migration. Cell Immunol 290:80-8
Garg, Koyal; Pullen, Nicholas A; Oskeritzian, Carole A et al. (2013) Macrophage functional polarization (M1/M2) in response to varying fiber and pore dimensions of electrospun scaffolds. Biomaterials 34:4439-51
Fernando, Josephine; Faber, Travis W; Pullen, Nicholas A et al. (2013) Genotype-dependent effects of TGF-*1 on mast cell function: targeting the Stat5 pathway. J Immunol 191:4505-13
Pullen, Nicholas A; Barnstein, Brian O; Falanga, Yves T et al. (2012) Novel mechanism for Fc{epsilon}RI-mediated signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation and the selective influence of STAT5B over mast cell cytokine production. J Biol Chem 287:2045-54
Falanga, Yves T; Chaimowitz, Natalia S; Charles, Nicolas et al. (2012) Lyn but not Fyn kinase controls IgG-mediated systemic anaphylaxis. J Immunol 188:4360-8
Kabolizadeh, Peyman; Engelmann, Brigitte J; Pullen, Nicholas et al. (2012) Platinum anticancer agents and antidepressants: desipramine enhances platinum-based cytotoxicity in human colon cancer cells. J Biol Inorg Chem 17:123-32

Showing the most recent 10 out of 18 publications