title: Induced loss of Syk in human basophils by non-IgE-dependent stimuli.
abstract: In the general population, Syk expression in human basophils is highly variable and correlates well with the IgE-mediated responsiveness of these cells. Previous studies established that IgE-mediated stimulation results in loss of Syk expression. The current studies investigated whether stimulation through other receptors results in loss of Syk. Two classes of stimulation were examined, those that operate through the kinase Syk and those that operate through a GTP-binding protein. These studies demonstrated that aggregation of leukocyte Ig-like receptor LILRA-2 resulted in phosphorylation of Syk and c-Cbl, was inhibited by a third generation Syk inhibitor with an expected IC(50), and induced histamine release in strict proportion to release induced by anti-IgE Ab. Stimulation of LILRA-2 for 18 h resulted in modest loss of Syk that correlated with the more profound loss of Syk induced by anti-IgE Ab. Human recombinant histamine-releasing factor has also recently been shown to induce Syk phosphorylation and in the current studies has also been shown to induce loss of Syk in 18-h cultures. fMLP stimulation for 18 h was also found to induce modest loss of Syk. fMLP induced phosphorylation of c-Cbl that was sustained for at least 45 min. Phosphorylation of c-Cbl was inhibited by a Syk kinase inhibitor but with an IC(50) that was not consistent with Syk activity, suggesting another kinase was responsible for Cbl phosphorylation following fMLP. These studies demonstrate that it is possible to induce the loss of Syk expression in human basophils by a non-IgE-dependent mechanism and even by a mechanism that does directly involve Syk in the reaction complex.
authors.affiliation: Asthma and Allergy Center, Johns Hopkins University, Baltimore, MD 21224, USA. dmacglas@jhmi.edu
authors.forename: Donald W
authors.initials: DW
authors.lastname: MacGlashan
authors.forename: Susan
authors.initials: S
authors.lastname: Ishmael
authors.forename: Susan M
authors.initials: SM
authors.lastname: MacDonald
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Langdon
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Arm
authors.forename: David E
authors.initials: DE
authors.lastname: Sloane
mesh_terms: D001491:Basophils / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D006636:Histamine Release / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000502:physiology; D007073:Immunoglobulin E / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D017455:Receptors, IgE / Q000502:physiology*; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase; D000090324:Tumor Protein, Translationally-Controlled 1
chemical_list: D014408:Biomarkers, Tumor; D007106:Immune Sera; D047908:Intracellular Signaling Peptides and Proteins; C105298:LILRA2 protein, human; D047428:Protein Kinase Inhibitors; D017455:Receptors, IgE; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D000090324:Tumor Protein, Translationally-Controlled 1; D007073:Immunoglobulin E; D009240:N-Formylmethionine Leucyl-Phenylalanine; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase