Neutrophil priming by cytokines and vitamin D binding protein (Gc-globulin): impact on C5a-mediated chemotaxis, degranulation and respiratory burst
Introduction
Infiltration of neutrophils and monocytes is a hallmark of virtually every inflammatory reaction (Snyderman and Uhing, 1992). In order to establish an effective inflammatory response, neutrophil functions have to be initiated in a strictly coordinated manner to eliminate invasive microorganisms and to avoid extensive damage to host tissues.
The complement-derived anaphylatoxin C5a represents one of the most potent mediators of inflammation (Ember et al., 1998, Gerard and Gerard, 1994). The 10 kD m.w. peptide is cleaved from the amino-terminal end of the complement component C5 through enzymes which are generated in the course of activation of either the classical, the alternative or the lectin pathways of the complement system (Rother et al., 1998). Like other chemoattractants, C5a elicits multiple effects on target cells, including chemotaxis, degranulation, oxidative burst, changes in adhesiveness as well as vasoconstriction, increased vascular permeability and smooth muscle contraction (Ember et al., 1998). Neutrophils detect a chemoattractant gradient through the regional difference in binding of the ligand to specific surface receptors. To maintain cell movement a certain amount of unoccupied receptors is required, which is provided by a continuous internalization upon ligand binding and reexpression (Zigmond, 1974). Mechanisms which transduce changes in C5a receptor occupancy into functional responses appear to involve one or more guanine nucleotide binding proteins (G proteins) (Buhl et al., 1994, Ye and Boulay, 1997).
Circulating neutrophils are continuously and simultaneously exposed to a vast array of stimulatory and inhibitory factors. These include cytokines, lipid mediators such as platelet activating factor (PAF), eicosanoids, bacteria-derived formylated peptides such as formyl-methionyl-leucyl-phenylalanine (FMLP), as well as molecules hitherto not known to be primarily involved in inflammation, such as the vitamin D binding protein (Gc-globulin). Low doses of one mediator which are not, or only weakly, effective to induce a certain cell response (e.g. chemotaxis) may enhance the effect of another mediator, a phenomenon occasionally termed as “priming” (Hallett and Lloyds, 1995). The need for a tight regulation of the neutrophil's proinflammatory response is best reflected by the potential of an agonist-induced attenuation of signalling (i.e. desensitization), as demonstrated for FMLP and C5a receptors (Didsbury et al., 1991). TNF-α, granulocyte/macrophage-CSF (GM-CSF), IL-1β, IFN-γ and PAF have been shown to prime neutrophils for FMLP-induced effector functions (Gay, 1990, Mikami et al., 1998, Tennenberg et al., 1993) and there is now a growing body of evidence that C5a-mediated neutrophil functions are also modulated by at least some of these molecules (Bajaj et al., 1992, Binder et al., 1996, Binder et al., 1999, Khwaja et al., 1992).
C5a is rapidly converted to C5desArg by the action of serum carboxypeptidase N which removes its carboxy-terminal arginine residue. Consequently, C5adesArg is about 100-fold less active than C5a in provoking neutrophil and monocyte chemotaxis. However, C5adesArg appears to represent the major complement-derived chemoattractant in serum due to the presence of a “cochemotactic factor” (Perez et al., 1981), later identified as Gc-globulin (Kew and Webster, 1988, Perez et al., 1988).
Section snippets
Impact of cytokines on C5a-mediated neutrophil functions
C5a exerts a strong chemotactic activity for neutrophils at concentrations of 1–10 nM. For the induction of maximal degranulation, a 10–100-fold higher concentration of the peptide is needed as compared to that for maximal chemotactic response. TNF-α as well as GM-CSF, which do not exert a significant direct chemotactic or release effect, where previously shown to enhance FMLP-induced degranulation and oxidative burst (Atkinson et al., 1990, Liles et al., 1995, Weisbart et al., 1987) but to
Selective impact of vitamin D-binding protein on C5a/C5adesArg-mediated chemotaxis
Gc-globulin is one of the most polymorphic serum proteins in man (Constans, 1992). In addition to three common alleles, i.e. Gc∗1F, Gc∗1S and Gc∗2, more than 120 rare alleles have been found (Braun et al., 1990, Cleve and Constans, 1988). Besides high concentrations in plasma (about 0.4 mg/ml) and its presence in various body fluids, such as cerebrospinal fluid and saliva, a cell-associated form of Gc-globulin has been found on diverse cell types (e.g. T and B lymphocytes, kidney cells).
Conclusion
Leukocytes exposed to a variety of humoral and cell-derived peptides need to react in a coordinated manner to perform an organized inflammatory reaction sequence. Underlying molecular mechanisms of priming, which can be considered as a transitional intermediate or preactivated stage of the cell are still obscure. The balance of concentrations of chemoattractants with their modulators within the microenvironment will determine the sequence of cell functions required to perform a coordinated
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