Comparison of Fc epsilon RI- and Fc gamma RI-mediated degranulation and TNF-alpha synthesis in human mast cells: selective utilization of phosphatidylinositol-3-kinase for Fc gamma RI-induced degranulation.
We have demonstrated that CD34(+) IFN-gamma-treated human mast cells (HuMC) express functional Fc gamma RI and that aggregation of these receptors leads to mediator release. As the signaling pathways linking Fc gamma RI aggregation to mediator release are unknown, we examined Fc gamma RI-dependent activation of specific signal transduction molecules and determined the relative involvement of these events in HuMC degranulation and TNF-alpha production following both Fc gamma RI and Fc epsilon RI aggregation. Fc gamma RI aggregation resulted in the phosphorylation/activation of src kinases and p72(syk) and subsequent tyrosine phosphorylation of multiple substrates. Inhibitor studies revealed that these responses were required for degranulation and TNF-alpha synthesis. Both Fc gamma RI and Fc epsilon RI aggregation also activated the MAP kinases ERK 1/2, JNK and p38 and this was necessary for TNF-alpha synthesis, but not degranulation for both receptors. Thus, signaling events in HuMC following aggregation of Fc gamma RI were generally similar to those observed following Fc epsilon RI aggregation. The one exception was that, although phosphatidylinositol-3-kinase was activated after both Fc epsilon RI and Fc gamma RI aggregation, only the Fc gamma RI appeared to require this molecule for degranulation.
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11C206, 10 Center Drive MSC 1881, Bethesda, MD 20892-1881, USA.
Yoshimichi
Y
Okayama
Christine
C
Tkaczyk
Dean D
DD
Metcalfe
Alasdair M
AM
Gilfillan
D000818:Animals; D015550:Cell Degranulation / Q000502:physiology*; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017455:Receptors, IgE / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D017455:Receptors, IgE; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases