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Multiple Defects in FcεRI Signaling in Syk-Deficient Nonreleaser Basophils and IL-3-Induced Recovery of Syk Expression and Secretion

2000; American Association of Immunologists; Volume: 165; Issue: 10 Linguagem: Inglês

10.4049/jimmunol.165.10.5913

1550-6606

Christopher L. Kepley, Lama A. Youssef, Ronald P. Andrews, Bridget S. Wilson, Janet M. Oliver,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

Abstract Human basophils respond to Ag-induced cross-linking of their high affinity IgE receptor, FcεRI, by releasing histamine and other mediators from granules, producing IL-4 and other cytokines and, as shown in this study, by forming membrane ruffles and showing increased very late Ag-4 (VLA-4)-mediated adhesion to VCAM-1-expressing target cells. We have identified five blood donors whose basophils lack detectable levels of the FcεRI-associated protein tyrosine kinase, Syk. Despite showing no obvious ultrastructural differences from normal basophils, nonreleaser basophils fail to form membrane ruffles, to show increased VLA-4-mediated adhesive activity, or to produce IL-4 in response to FcεRI cross-linking. Although Syk protein levels are suppressed in basophils from all five donors, Syk mRNA is consistently present. Furthermore, culturing nonreleaser basophils for 4 days with IL-3 restores Syk protein expression and FcεRI-mediated histamine release. Understanding the reversible suppression of Syk protein expression in nonreleaser basophils, and learning to replicate this property in patients with allergic inflammation could be a powerful and specific way to limit symptomatic disease.