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Impaired degranulation but enhanced cytokine production after FcRI stimulation of diacylglycerol kinase –deficient mast cells

¹ The Signal Transduction Program, The Abramson Family Cancer Research Institute and ² The Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
³ Department of Pediatrics and ⁴ Department of Immunology, Duke University Medical Center, Durham, NC 27710

CORRESPONDENCE Gary Koretzky: koretzky{at}mail.med.upenn.edu OR Xiao-Ping Zhong: zhong001{at}mc.duke.edu

Calcium and diacylglycerol are critical second messengers that together effect mast cell degranulation after allergen cross-linking of immunoglobulin (Ig)E-bound FcRI. Diacylglycerol kinase (DGK) is a negative regulator of diacylglycerol-dependent signaling that acts by converting diacylglycerol to phosphatidic acid. We reported previously that DGK^–/– 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^–/– bone marrow–derived mast cells (BMMCs) demonstrate impaired degranulation after FcRI cross-linking, associated with diminished phospholipase C activity, calcium flux, and protein kinase C–ßII membrane recruitment. In contrast, Ras-Erk signals and interleukin-6 production are enhanced, both during IgE sensitization and after antigen cross-linking of FcRI. 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 FcRI signals.

Abbreviations used: BMMC, bone marrow–derived cell; DAG, diacylglycerol; DGK, DAG kinase; IP₃, inositol 1,4,5-trisphosphate; LAT, linker for activated T cells; MAPK, mitogen-activated protein kinase; PA, phosphatidic acid; PCA, passive cutaneous anaphylaxis; PI5K, phosphatidylinositol 4-phosphate 5-kinase; PIP₂, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C.

B.A. Olenchock and R. Guo contributed equally to this work.

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