Impaired degranulation but enhanced cytokine production after FcεRI stimulation of diacylglycerol kinase ξ-deficient mast cells

Calcium and diacylglycerol are critical second messengers that together effect mast cell degranulation after allergen cross-linking of immunoglobulin ( Ig) E-bound Fc epsilon RI. Diacylglycerol kinase ( DGK)zeta is a negative regulator of diacylglycerol-dependent signaling that acts by converting diacylglycerol to phosphatidic acid. We reported previously that DGK zeta(-/-) mice have enhanced in vivo T cell function. Here, we demonstrate that these mice have diminished in vivo mast cell function, as revealed by impaired local anaphylactic responses. Concordantly, DGK zeta(-/-) bone marrow-derived mast cells ( BMMCs) demonstrate impaired degranulation after Fc epsilon RI cross-linking, associated with diminished phospholipase C gamma activity, calcium flux, and protein kinase C-beta II membrane recruitment. In contrast, Ras-Erk signals and interleukin-6 production are enhanced, both during IgE sensitization and after antigen cross-linking of Fc epsilon RI. Our data demonstrate dissociation between cytokine production and degranulation in mast cells and reveal the importance of DGK activity during IgE sensitization for proper attenuation of Fc epsilon RI signals.