Impaired degranulation but enhanced cytokine production after Fc epsilonRI stimulation of diacylglycerol kinase zeta-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 FcepsilonRI. Diacylglycerol kinase (DGK)zeta is a negative regulator of diacylglycerol-dependent signaling that acts by converting diacylglycerol to phosphatidic acid. We reported previously that DGKzeta-/- 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, DGKzeta-/- bone marrow-derived mast cells (BMMCs) demonstrate impaired degranulation after Fc epsilonRI cross-linking, associated with diminished phospholipase Cgamma activity, calcium flux, and protein kinase C-betaII membrane recruitment. In contrast, Ras-Erk signals and interleukin-6 production are enhanced, both during IgE sensitization and after antigen cross-linking of Fc epsilonRI. 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 epsilonRI signals.
Olenchock
Benjamin A
BA
The Signal Transduction Program, The Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Guo
Rishu
R
Silverman
Michael A
MA
Wu
Jennifer N
JN
Carpenter
Jeffery H
JH
Koretzky
Gary A
GA
Zhong
Xiao-Ping
XP
D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000096:biosynthesis*; D017931:DNA Primers; D019852:Diacylglycerol Kinase / Q000172:deficiency*; D005434:Flow Cytometry; D015850:Interleukin-6 / Q000276:immunology; D008407:Mast Cells / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D010323:Passive Cutaneous Anaphylaxis / Q000276:immunology*; D016133:Polymerase Chain Reaction; D017455:Receptors, IgE / Q000276:immunology*
D016207:Cytokines; D017931:DNA Primers; D015850:Interleukin-6; D017455:Receptors, IgE; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse