Elsevier

Molecular Immunology

Volume 36, Issues 13–14, September–October 1999, Pages 885-892
Molecular Immunology

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

https://doi.org/10.1016/S0161-5890(99)00110-8Get rights and content

Abstract

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-α 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/C5adesArg. In contrast, TNF-α 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.

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. Gc1F, Gc1S and Gc2, 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

References (60)

  • M.W. Wooten et al.

    Identification of a major endogenous substrate for phospholipid/Ca2±dependent kinase in pancreatic acini as Gc (vitamin D-binding protein)

    FEBS Lett.

    (1985)
  • R.D. Ye et al.

    Structure and function of leukocyte chemoattractant receptors

    Adv. Pharmacol.

    (1997)
  • A. Yuo et al.

    Stimulation and priming of human neutrophils by interleukin-8: cooperation with tumor necrosis factor and colony-stimulating factors

    Blood

    (1991)
  • Y.H. Atkinson et al.

    Recombinant human granulocyte-macrophage colony-stimulating factor (rH GM-CSF) regulates f Met-Leu-Phe receptors on human neutrophils

    Immunology

    (1988)
  • Y.H. Atkinson et al.

    Recombinant human tumor necrosis factor-alpha. Regulation of N-formylmethionylleucylphenylalanine receptor affinity and function on human neutrophils

    J. Clin. Invest.

    (1988)
  • Y.H. Atkinson et al.

    Human tumour necrosis factor-alpha (TNF-alpha) directly stimulates arachidonic acid release in human neutrophils

    Immunology

    (1990)
  • M.S. Bajaj et al.

    Priming of human neutrophil functions by tumor necrosis factor: enhancement of superoxide anion generation, degranulation, and chemotaxis to chemoattractants C5a and F-Met-Leu-Phe

    Inflammation

    (1992)
  • R. Binder et al.

    Modulation of C5a-induced neutrophil activation by tumor necrosis factor alpha (TNFα) and granulocyte/macrophage colony stimulating factor (GM-CSF)

    Immunobiology

    (1996)
  • Binder, R., Kress, A., Kirschfink, M., 1999. Modulation of C5a-induced neutrophil activation by tumor necrosis factor...
  • A. Braun et al.

    Interaction of the vitamin D-binding protein (group-specific component) and its ligand 25-hydroxy-vitamin D3: binding differences of the various genetic types disclosed by isoelectric focusing

    Electrophoresis

    (1990)
  • A.M. Buhl et al.

    Mapping of the C5a receptor signal transduction network in human neutrophils

    Proc. Natl. Acad. Sci. USA

    (1994)
  • H. Cleve et al.

    The mutants of the vitamin-D-binding protein: more than 120 variants of the GC/DBP system

    Vox Sang.

    (1988)
  • A.M. Condliffe et al.

    Priming differentially regulates neutrophil adhesion molecule expression/function

    Immunology

    (1996)
  • J. Constans

    Group-specific component is not only a vitamin-D-binding protein

    Exp. Clin. Immunogenet.

    (1992)
  • M.S. Currie et al.

    Stimulus-specific effects of pentoxifylline on neutrophil CR3 expression, degranulation, and superoxide production

    J. Leuk. Biol.

    (1990)
  • J.R. Didsbury et al.

    Receptor class desensitization of leukocyte chemoattractant receptors

    Proc. Natl. Acad. Sci. USA

    (1991)
  • H.G. Dohlman et al.

    Model systems for the study of seven-transmembrane-segment receptors

    Annu. Rev. Biochem.

    (1991)
  • S. Dunzendorfer et al.

    Pentoxifylline differentially regulates migration and respiratory burst activity of the neutrophil

    Ann. NY Acad. Sci.

    (1997)
  • J.A. Ember et al.

    Characterization of complement anaphylatoxins and their biological responses

  • D. English et al.

    Temporal adaptation of neutrophil oxidative responsiveness to n-formyl-methionyl-leucyl-phenylalanine. Acceleration by granulocyte-macrophage colony stimulating factor

    J. Immunol.

    (1988)
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