Relationship between spleen tyrosine kinase and phosphatidylinositol 5′ phosphatase expression and secretion from human basophils in the general population

Abstract

Previous studies have suggested that expression levels of spleen tyrosine kinase (syk) or phosphatidylinositol 5' phosphatase (SHIP) may explain certain extreme human basophil phenotypes. This study is designed to explore whether variability in syk and SHIP expression levels in the general population, alone or in concert, can account for the variability in basophil function. A survey of maximum responsiveness to IgE-mediated stimulation, sensitivity, and expression levels of 6 early signaling elements was performed on 36 subjects' basophils. Of the 6 signaling elements, only syk and SHIP showed a correlation with maximum histamine release or cellular sensitivity. In a multiple regression, syk and SHIP together could account for 67% of population variance, although most of the variance was explained by syk expression. The pattern of expression variance syk>>SHIP1>SHIP2 approximately lyn approximately p85 approximately cbl suggested a process that primarily modulated syk levels. IL-3 is known to modulate syk levels, but we found that a 3-day incubation with IL-3 resulted in increased expression of other signaling elements to a greater degree: cbl>SHIP1>SHIP2 approximately lyn approximately p85 > or = syk, opposite the pattern in the population survey. In contrast, 18-hour stimulation with anti-IgE antibody led to marked downregulation of syk expression, modest downregulation of Fc epsilon RI expression, weak downregulation of lyn expression, and no effect on 23 other signaling elements. Unlike studies in mice, we conclude that expression of syk is a good preconditioning predictor of basophil function in the general population. The finding that expression of syk levels may strongly influence functional responses of basophils suggests a mechanism underlying the severity of atopic diseases.