Mast cells are critical effectors of allergic disease that can be activated by numerous stimuli. We have examined mast cell control by the inflammatory cytokine, IL-33, as well as IgG. In the first study reported here, we found that the synthetic glucocorticoid, dexamethasone, potently and rapidly suppressed IL-33-induced cytokine production from murine bone marrow–derived and peritoneal mast cells, as well as human mast cells. Dexamethasone also antagonized IL-33-mediated enhancement of IgE-induced cytokine production and migration. Although dexamethasone had no effect on IL-33-induced phosphorylation of MAP kinases or NFκB p65 subunit, it antagonized AP-1 and NFκB-mediated transcriptional activity. Finally, intraperitoneal administration of dexamethasone completely abrogated IL-33-mediated peritoneal neutrophil recruitment and prevented plasma IL-6 elevation. These data demonstrate that steroid therapy may be an effective means of antagonizing the effects of IL-33 on mast cells in vitro and in vivo, acting partly by suppressing IL-33-induced NFκB and AP-1 activity. In the second study reported here, we found that Fcγ receptor crosslinkage activated the transcription factor Stat5B through a Fyn kinase-dependent pathway. We then showed that STAT5B is critical for IgG-induced cytokine production by mast cells but not macrophages. To expand these studies, we employed the K/BxN model of inflammatory arthritis, which has roles for mast cells and macrophages. In this model, Fyn or STAT5B deficiency only affected the arthritic flare that primarily depends on mast cell degranulation, without affecting the severity of the joint swelling. By contrast, Lyn kinase deficiency significantly exacerbated arthritis. These studies indicate a clinically relevant, lineage-restricted role for the Lyn/Fyn-STAT5 cascade. Collectively, our work demonstrates that mast cell activation by diverse stimuli can be suppressed by steroid intervention and selectively targeted by disrupting kinase-transcription factor pathways.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-6149 |
| Date | 01 January 2017 |
| Creators | Paranjape, Anuya |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © Anuya Paranjape |
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