Neutrophil priming by cytokines and vitamin D binding protein (Gc-globulin): impact on C5a-mediated chemotaxis, degranulation and respiratory burst

At the site of acute inflammation, leukocytes are confronted with multiple mediators which are expected to modulate each other with respect to cell re sponses to the individual ligand. Previous contact of neutrophils with pro- inflammatory cytokines, such as TNF-alpha or GM-CSF, or with the vitamin D binding protein (Gc-globulin) leads to the alteration of either multiple or rather distinct C5a-mediated neutrophil functions. Gc-globulin, the transp ort protein for 25-(OH)-D-3, serves selectively as a cochemotactic factor f or C5a/C5a(desArg). In contrast, TNF-alpha and GM-CSF, previously shown to modulate FMLP-induced neutrophil responses, are able to reduce C5a-mediated neutrophil chemotaxis, but augment their degranulation and respiratory bur st activity. Cytokine priming was shown to be accompanied by a down-regulat ion of C5a receptors (CD88) whereas vitamin D binding protein had no impact on the level of neutrophil C5a receptors. C5a itself diminishes chemotaxis as well as degranulation and oxidative burst in response to a second dose of the same ligand (homologous desensitization). A similar effect, termed h eterologous desensitization, occurs, if cell responses to a given mediator (e.g. to C5a) are reduced or even abolished upon the activation of another receptor of the same G-protein coupled chemoattractant receptor subfamily ( e.g. receptors for FMLP or IL-8). In concert with C5a, certain molecules ma y either augment chemotaxis or shift neutrophil effector functions from mig ration to exocytosis, an essential step within the sequence of events in a coordinated inflammatory response. (C) 1999 Elsevier Science Ltd. All right s reserved.