Two Regions of Down-Regulation in the IgE-Mediated Signaling Pathway in Human Basophils

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Abstract
Previous studies demonstrated that after stimulation of human basophils with a polyclonal anti-IgE Ab, early signaling elements showed sustained phosphorylation, whereas later elements were transient, suggesting that a region of down-regulation involved inhibition of phosphatidylinositol (PI) 3 kinase or its products. However, the current studies show that under some conditions, syk phosphorylation is transient. Generally, stimulation with a variety of Ags makes this early form of down-regulation more apparent. An exploration of the conditions needed to induce early down-regulation indicates that both the nature of aggregation and the cell surface density of IgE play roles. It was also found that the previously described late form of down-regulation (PI3 kinase product transience) can occur in cells displaying early down-regulation (transient syk phosphorylation), but this phenomenon is revealed by testing for subsequent down-regulation of the response to non-cross-reacting stimuli, altering their ability to induce phosphorylation of Akt or extracellular signal-regulated kinase. In contrast, phosphorylation of syk kinase, in response to a non-cross-reacting stimulus, was relatively unaffected by prior stimulation. The magnitude of cross-desensitization of the Akt or extracellular signal-regulated kinase response was a function of the strength of the first stimulus. Mediator release showed a similar cross-desensitization effect. Therefore, stimulation induces two forms of down-regulation, one operating before or at the level of syk phosphorylation, possibly characterizing the process formerly known as specific desensitization, and one that operates in the region of PI3 kinase, accounting for the process formerly known as nonspecific desensitization, which is dependent on the strength of stimulus.