Increased expression of genes linked to FcεRI signaling and to cytokine and chemokine production in Lyn-deficient mast cells

Cross-linking the high-affinity IgE receptor, FC epsilon RI, on mast cells activates signaling pathways leading to the release of preformed inflammatory mediators and the production of cytokines and chemokines associated with allergic disorders. Bone marrow-derived mast cells (BMMCs) from Lyn-deficient (Lyn(-/-)) mice are hyperresponsive to FC epsilon RI cross-linking with multivalent Ag. Previous studies linked the hyperresponsive phenotype in part to increased Fyn kinase activity and reduced SHIP phosphatase activity in the Lyn(-/-) BMMCs in comparison with wild-type (WT) cells. In this study, we compared gene expression profiles between resting and Ag-activated WT and Lyn(-/-) BMMCs to identify other factors that may contribute to the hyperresponsiveness of the Lyn(-/-) cells. Among genes implicated in the positive regulation of FC epsilon RI signaling, mRNA for the tyrosine kinase, Fyn, and for several proteins contributing to calcium regulation are more up-regulated following Ag stimulation in Lyn(-/-) BMMCs than in WT BMMCs. Conversely, mRNA for the low-affinity IgG receptor (Fc gamma RIIB), implicated in negative regulation of Fc epsilon RI-mediated signaling, is more down-regulated in Ag-stimulated l,yn(-/-) BMMCs than in WT BMMCs. Genes coding for proinflammatory cytokines and chemokines (IL-4,IL-6,IL-13, CSF, CCL1, CCL3, CCL5, CCL7, CCL9, and MIPI beta) are all more highly expressed in Ag-stimulated Lyn(-/-) mast cells than in WT cells. These microarray data identify Lyn as a negative regulator in Ag-stimulated BMMCs or the expression of genes linked to FC epsilon RI signaling and also to the response pathways that lead to allergy and asthma.