Intracellular control of human neutrophil secretion. II. Stimulus specificity of desensitization induced by six different soluble and particulate stimuli.

Stimulation of inflammatory cells, including neutrophils, may lead both to activation and to a process of desensitization, or “down regulation,” which, it is hypothesized, may serve as a regulatory mechanism to limit the extent of activation. Pretreatment of neutrophils with C5a before incubation with cytochalasin B was earlier shown to prevent the granule exocytosis (i.e., the release of myeloperoxidase and lysozyme) initiated by a subsequent interaction with C5a. This state of desensitization has here been shown to exhibit considerable stimulus specificity. C5a-desensitized neutrophils respond normally to aggregated immunoglobulin, casein, bacterial factor, and opsonized zymosan but exhibit reduced responsiveness to the tripeptide f-methionyl-leucyl-phenylalanine (FMLP). In the reverse situation, FMLP induced desensitization to the subsequent addition of FMLP but also a partial desensitization to C5a. Such cells were still responsive to aggregated immunoglobulin, casein, and opsonized zymosan. Aggregated immunoglobulin also caused stimulus-specific unresponsiveness, in this case both to soluble and insoluble aggregated immunoglobulin; the latter was also examined in the absence of cytochalasin B. Only slight cross-desensitization was seen between aggregated immunoglobulin and serum-opsonized zymosan, which suggests an immunoglobulin-independent stimulus on this particle. It is concluded that the induction of desensitization occurs at the stimulus-specific step(s) in the stimulus-secretion coupling pathway and that triggering of a number of different neutrophil membrane “receptors” can lead to granule exocytosis.