SLP-76 deficiency impairs signaling via the high-affinity IgE receptor in mast cells.
SLP-76 is an adapter protein expressed in T cells and myeloid cells that is a substrate for ZAP-70 and Syk. SLP-76-deficient mice exhibit a profound block in T-cell development. We found that although SLP-76 is expressed in mouse mast cells, SLP-76(-/-) mice have normal numbers of mast cells in their skin and bronchi. SLP-76(-/-) mice are resistant to IgE-mediated passive anaphylaxis. SLP-76(-/-) mice sensitized with IgE anti-dinitrophenyl (DNP) and then challenged with DNP-HSA developed only mild and transient tachycardia, failed to increase their plasma histamine level, and all survived the antigen challenge. Bone marrow-derived mast cells (BMMCs) from SLP76(-/-) mice failed to release beta-hexosaminidase and to secrete IL-6 after FcepsilonRI cross-linking. Tyrosine phosphorylation of phospholipase C-gamma1 (but not of Syk) and calcium mobilization in response to IgE cross-linking were reduced in SLP-76-deficient BMMCs. These results suggest that SLP-76 plays an important role in FcepsilonRI-mediated signaling in mast cells.
Pivniouk
V I
VI
Division of Immunology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Martin
T R
TR
Lu-Kuo
J M
JM
Katz
H R
HR
Oettgen
H C
HC
Geha
R S
RS
D048868:Adaptor Proteins, Signal Transducing; D019264:Adoptive Transfer; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D015550:Cell Degranulation / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D007073:Immunoglobulin E / Q000008:administration & dosage / Q000502:physiology; D008407:Mast Cells / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010323:Passive Cutaneous Anaphylaxis; D010750:Phosphoproteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D010750:Phosphoproteins; D017455:Receptors, IgE; C092947:SLP-76 signal Transducing adaptor proteins; D007073:Immunoglobulin E