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 responses 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 transport protein for 25-(OH)-D3, serves selectively as a cochemotactic factor for C5a/Ca(des)Arg. 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 burst activity. Cytokine priming was shown to be accompanied by a down-regulation 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 heterologous 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 may either augment chemotaxis or shift neutrophil effector functions from migration to exocytosis, an essential step within the sequence of events in a coordinated inflammatory response.
Binder
R
R
Institute of Immunology, University of Heidelberg, Germany.
Kress
A
A
Kan
G
G
Herrmann
K
K
Kirschfink
M
M
D015550:Cell Degranulation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015936:Complement C5a / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects; D014809:Vitamin D-Binding Protein / Q000378:metabolism* / Q000494:pharmacology
D016207:Cytokines; D018836:Inflammation Mediators; D014809:Vitamin D-Binding Protein; D015936:Complement C5a