Impaired FcεRI-dependent gene expression and defective eicosanoid and cytokine production as a consequence of fyn deficiency in mast cells

Fyn kinase is a key contributor in coupling Fc epsilon RI to mast cell degranulation. A limited macroarray analysis of Fc epsilon RI-induced gene expression suggested potential defects in lipid metabolism, eicosanoid and glutathione metabolism, and cytokine production. Biochemical analysis of these responses revealed that Fyn-deficient mast cells failed to secrete the inflammatory eicosanoid products leukotrienes B-4 and C-4, the cytokines IL-6 and TNF, and chemokines CCL2 (MCP-1) and CCL4 (MIP-1 beta). Fc epsilon RI-induced generation of arachidonic acid and normal induction of cytokine mRNA were defective. Defects in JNK and p38 MAPK activation were observed, whereas ERK1/2 and cytosolic phospholipase A(2) (S505) phosphorylation was normal. Pharmacological studies revealed that JNK activity was associated with generation of arachidonic acid. Fc epsilon RI-mediated activation of I kappa B kinase 13 and 1 kappa B alpha phosphorylation and degradation was defective resulting in a marked decrease of the nuclear NF-kappa B DNA binding activity that drives IL-6 and TNF production in mast cells. However, not all cytokine were affected, as IL-13 production and secretion was enhanced. These studies reveal a major positive role for Fyn kinase in multiple mast cell inflammatory responses and demonstrate a selective negative regulatory role for certain cytokines.