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PubMed1991

[The relationship between complement C3 receptors (CR1, CR3) on polymorphonuclear leukocytes and complement fragments during hemodialysis].

The expression of complement receptor type 1 (CR1) and type 3 (CR3) on polymorphonuclear leukocytes (PMNs) and generation of complement fragments, C3a, C5a, C4d, iC3b and Bb, were studied in patients during hemodialysis using cuprammonium rayon (Cu) membranes. Furthermore, the relation between the expression of CR1 and CR3 on PMNs from healthy donors and complement fragments was investigated. The expression of CR1 and CR3 on PMNs increased during hemodialysis. Plasma C3a, C5a and iC3b levels increased in the first 15 minutes and then decreased at 120 minutes of dialysis. But plasma Bb level remained high until the end of hemodialysis. Purified Bb had no effect on the expression of CR1 and CR3 on PMNs, but C5a augmented those expression in vitro. Nafamostat mesilate, an artificial proteinase inhibitor, inhibited augmentation of complement receptors on PMNs in concentration dependent fashion. C5a generated through the activation of complement was thought to take an important role in the increased expression of CR1 and CR3 on PMNs.

Aged↗
PubMed2000

Cutting edge: guinea pigs with a natural C3a-receptor defect exhibit decreased bronchoconstriction in allergic airway disease: evidence for an involvement of the C3a anaphylatoxin in the pathogenesis of asthma.

Asthma is a major cause of morbidity worldwide with prevalence and severity still increasing at an alarming pace. Hallmarks of this disease include early-phase bronchoconstriction with subsequent eosinophil infiltration, symptoms that may be mimicked in vivo by the complement-derived C3a anaphylatoxin, following its interaction with the single-copy C3aR. We analyzed the pathophysiological role of the C3a anaphylatoxin in a model of experimental OVA-induced allergic asthma, using an inbred guinea pig strain phenotypically unresponsive to C3a. Molecular analysis of this defect revealed a point mutation within the coding region of the C3aR that creates a stop codon, thereby effectively inactivating gene function. When challenged by OVA inhalation, sensitized animals of this strain exhibited a bronchoconstriction decreased by approximately 30% in comparison to the corresponding wild-type strain. These data suggest an important role of C3a in the pathogenesis of asthma and define a novel target for drug intervention strategies.

Administration, Inhalation↗
PubMed1983

Human platelet activation by C3a and C3a des-arg.

C3a liberated from C3 by treatment with C3 convertase (or by trypsin) induced aggregation of gel-filtered human platelets and stimulated serotonin release. At concentrations of 10(-10) M to 8 X 10(-12) M, C3a induced aggregation when added alone to platelets. However, at lower concentrations (2 X 10(-12) M) C3a did not aggregate platelets directly but exhibited highly significant synergism (two-way analysis of variance P less than 0.0001) with ADP in mediating platelet aggregation and release of serotonin. Removal of the C-terminus arginine from C3a abolished anaphylotoxin activity but did not affect the platelet-stimulating activity of the peptide. C3a and C3a des-arg were equally reactive in mediating platelet aggregation and release of serotonin. Further C3a and C3a des-arg exhibited synergism with ADP of equal significance in both aggregation and the release reaction. The concentrations of C3a required for the platelet-stimulating activity involve relatively small number of molecules per platelet (4,000-10,000 for the synergistic reaction with ADP). These data suggest the possibility of a C3a (C3a des-arg) receptor on human platelets. This premise is strengthened by the demonstration ultrastructurally of C3a on the platelet membrane subsequent to C3a stimulation.

Adenosine Diphosphate↗
PubMed1986

Complement activation during systemic lupus erythematosus. C3a and C5a anaphylatoxins circulate during exacerbations of disease.

To determine whether activated complement components appear in the circulation of patients with systemic lupus erythematosus (SLE), we measured C5a and C3a by radioimmunoassay. Mean C5a concentration in the plasma of acutely ill SLE patients was 46.0 ng/ml, compared with 17.1 ng/ml in normal controls (P less than 0.01). Mean C3a concentration in patients with severe disease was 526 ng/ml, compared with 134 ng/ml in controls (P less than 0.01). In patients with moderately active SLE, the mean C3a concentration, but not the mean C5a concentration, was also elevated. In addition, C3a was elevated in 15 or 21 patients with active SLE, whereas low levels of C3 or C4 were noted in only 7 of these 21 patients. We conclude that the measurement of complement-derived anaphylatoxins may be useful in the management of patients with SLE. In addition, we suggest that these circulating mediators may contribute to the pathogenesis of vascular injury in patients with the disease.

Complement Activation↗
PubMed1981

Comparative study on biological activities of various anaphylatoxins (C4a, C3a, C5a). Investigations on their ability to induce platelet secretion.

Several anaphylatoxic substances (human C3a, guinea pig C3a, human C4a, guinea pig C5a, and a synthetic C3a-related hexapeptide) were compared with regard to their ability to induce secretion of [3H] serotonin from guinea pig platelets. Functional identity of the C3a preparations, C4a, and the hexapeptide was demonstrated by the phenomenon of crossed desensitization. Whereas C3a of human and guinea pig origin proved to be qualitatively and quantitatively identical, C4a expressed only 3% of the activity of the C3 fragments on a molar basis. Investigations with goat anti-guinea pig C3a demonstrate that human and guinea pig C3a possess one antigenic determinant in common; however, this determinant is not the C-terminal amino acid sequence. Addition of the anaphylatoxins with low doses of thrombin led to a potentiation of [3H] serotonin release from the platelets. Under these conditions C3a concentrations of 1.5 X 10(-10) mumol/liter (65 pg of C3a) could be detected. Thus the platelet system represents the most sensitive in vitro assay known for evaluation of biological activity of the C3a anaphylatoxins.

Anaphylatoxins↗
PubMed1995

C3a is a chemotaxin for human eosinophils but not for neutrophils. I. C3a stimulation of neutrophils is secondary to eosinophil activation.

Inflammatory action of the potent chemotaxin C5a has been well characterized on a variety of human cell types, including neutrophils, monocytes, basophils, and eosinophils. The cellular effects of C3a are less well defined. Contradictory reports have been published for C3a activation of neutrophils. Recent reports that C3a activates both basophils and eosinophils prompted us to reinvestigate the effects of C3a stimulation on eosinophils. We hypothesized that C3a activation of eosinophils, cells that are present in most neutrophil preparations, might lead to neutrophil activation. Using neutrophils of 98% purity, we observed no evidence of cellular activation after stimulation with either C3a, recombinant human C3a (rhC3a), or the synthetic C3a analogue C3a 57-77, Y57. Eosinophils purified to > 98% purity displayed concentration-dependent polarization, chemotaxis, and enzyme release by stimulation with C3a, rhC3a, and the synthetic C3a analogue. An inactive form of C3a, C3adesArg, failed to stimulate either eosinophils or neutrophils. Using neutrophil preparations containing 5-9% eosinophils, up to 20% of neutrophils became polarized after exposure to C3a. Likewise, we demonstrated that supernatant from C3a-stimulated eosinophils promotes neutrophil chemotaxis. Eosinophil polarization experiments were repeated in the presence of antibody to the C5a receptor (C5aR) to show that C3a and C5a interact with different receptors. C3a activates eosinophils in the presence of anti-C5aR antibody at concentrations that fully block C5a activation. We conclude that eosinophils are directly activated by either C3a or C5a, whereas C3a failed to activate neutrophils. C3a acts on eosinophils via a receptor that is distinct from C5aR. Since neutrophils are indirectly stimulated by C3a, eosinophils contaminating neutrophil preparations may explain earlier reports that C3a activates human neutrophils.

Amino Acid Sequence↗
PubMed1990

Anaphylatoxins C3a and C5a adsorption on acrylonitrile membrane of hollow-fiber and plate dialyzer--an in vivo study.

We studied the adsorption of anaphylatoxins C3a and C5a on acrylonitrile (AN69) hollow-fiber (AN69HF) and plate (AN69P) dialyzers in 8 patients during 4-hour hemodialyses (HD). Blood passed first through a cuprophan dialyzer and then through AN69 dialyzers that were not in contact with dialysis fluid. Plasma C3a and C5a were measured in samples taken from the afferent and efferent blood lines of the acrylonitrile dialyzers at 15, 60 and 240 min. Plasma C3a concentrations decreased significantly in blood that had passed through AN69 dialyzers. This decrease, indicating membrane adsorption, was maximal (by 65% in AN69HF and by 59% in AN69P) at 15 min and minimal (by 53% in AN69HF and by 18% in AN69P) at 240 min. The decrease in plasma C5a concentrations was smaller and significant throughout HD only with AN69HF. The amount of C3a adsorbed was at least 45,000 micrograms in AN69HF and 18,000 micrograms in AN69P. These findings demonstrate that acrylonitrile dialyzers adsorb more C3a and C5a than they produce. This membrane adsorption may explain why the increase of plasma C3a and C5a is inhibited during HD.

Acrylonitrile↗
PubMed2004

C3a enhances nerve growth factor-induced NFAT activation and chemokine production in a human mast cell line, HMC-1.

Activation of cell surface G protein-coupled receptors leads to transphosphorylation and activation of a number of receptor tyrosine kinases. Human mast cells express G protein-coupled receptors for the complement component C3a (C3aR) and high affinity nerve growth factor (NGF) receptor tyrosine kinase, TrkA. To determine whether C3a cross-regulates TrkA signaling and biological responses, we used a human mast cell-line, HMC-1, that natively expresses both receptors. We found that NGF caused tyrosine phosphorylation of TrkA, resulting in a sustained Ca(2+) mobilization, NFAT activation, extracellular-signal regulated kinase (ERK) phosphorylation, and chemokine, macrophage inflammatory protein-1beta (MIP-1beta) production. In contrast, C3a induced a transient Ca(2+) mobilization and ERK phosphorylation but failed to stimulate TrkA phosphorylation, NFAT activation, or MIP-1beta production. Surprisingly, C3a significantly enhanced NGF-induced NFAT activation, ERK phosphorylation, and MIP-1beta production. Pertussis toxin, a G(i/o) inhibitor, selectively blocked priming by C3a but had no effect on NGF-induced responses. Mitogen-activated protein/ERK kinase inhibitor U0126 caused approximately 30% inhibition of NGF-induced MIP-1beta production but had no effect on priming by C3a. However, cyclosporin A, an inhibitor of calcineurin-mediated NFAT activation, caused substantial inhibition of NGF-induced MIP-1beta production both in the absence and presence of C3a. These data demonstrate that NGF caused tyrosine phosphorylation of TrkA to induce chemokine production in HMC-1 cells via a pathway that mainly depends on sustained Ca(2+) mobilization and NFAT activation. Furthermore, C3a enhances NGF-induced transcription factor activation and chemokine production via a G protein-mediated pathway that does not involve TrkA phosphorylation.

Calcium↗
PubMed1994

Activation of human neutrophils by C3a and C5A. Comparison of the effects on shape changes, chemotaxis, secretion, and respiratory burst.

The effects of anaphylatoxin C3a on human neutrophils were studied in comparison with C5a. Both peptides induced a transient shape change response and a respiratory burst. In both cases C3a was 50- to 100-times less potent than C5a. A marked chemotactic response with bimodal concentration dependence was obtained with C5a, but no neutrophil chemotaxis was observed with C3a. Repeated stimulation led to homologous desensitization of shape changes and respiratory burst but no cross-desensitization, indicating that the two anaphylatoxins act through separate receptors. The lack of chemotactic activity suggests that C3a is not involved in neutrophil recruitment into infected or inflamed tissues.

Chemotaxis, Leukocyte↗
PubMed1993

Measurement of anaphylatoxin activity during surgery.

We studied whether or not anaphylatoxins (ATs) are related to stress-related surgery by examining AT measurement in 51 patients undergoing operation. C3a plasma levels in patients who underwent the Caldwell-Luc operation increased from a pre-surgery concentration of 129 +/- 19 (mean +/- SD) ng/ml to 293 +/- 91 ng/ml during surgery under local anesthesia. However, pre- and post-surgery values were almost the same. No significant change occurred in the C5a plasma concentration at any time in patients undergoing the Caldwell-Luc operation, tonsillectomy or partial glossectomy. The mechanism underlying elevation in C3a during surgery is discussed.

Adult↗
PubMed1998

Anaphylatoxins C5a and C3a induce nuclear factor kappaB activation in human peripheral blood monocytes.

The anaphylatoxins C5a and C3a are involved in the regulation of cytokine production. In this study the capability of C5a and C3a to induce transcription factor activation was examined. C5a and C3a stimulation of human peripheral blood monocytes resulted in nuclear expression of a DNA binding activity with specificity to the kappaB sequence. The p50 and p65 proteins, constituents of the prototypic nuclear factor kappaB, were identified as components of the DNA-protein complexes by anti-peptide antibodies in gel supershift assays. C5a induced kappaB binding activity was detected 15 min after agonist stimulation, peaked at 30-40 min, and remained detectable at 2 h. Binding to kappaB sequence was accompanied by an initial decrease and subsequent increase in the cytoplasmic IkappaBalpha levels, as detected by Western blotting using an anti-IkappaBalpha antibody. Pertussis toxin treatment markedly decreased kappaB binding activities induced by both C5a and C3a, whereas cholera toxin displayed no inhibitory effect. Neither of the two toxins affected kappaB binding activity induced by TNFalpha in the same cells. These results imply a potential role of the anaphylatoxins C5a and C3a in regulating leukocytes gene expression through G protein-coupled transcription factor activation.

Bacterial Toxins↗
PubMed1993

Chronic myelogenous leukemia-derived basophilic granulocytes express a functional active receptor for the anaphylatoxin C3a.

The receptor for the inflammatory peptide C3a has scarcely been examined on human cells. This work demonstrates that human tumor-derived basophilic granulocytes express C3a receptors, and presents parts of the hitherto unknown C3a-signal transduction. When incubated with IL-3, these cells specifically liberated histamine on C3a stimulation. Independent from IL-3, 240,000 +/- 100,000 receptors per cell with a Kd of 5.6 +/- 0.9 nM were determined. [Ca2+]i increased from 120 +/- 35 nM to 300 +/- 80 nM after a C3a challenge, as measured by digital imaging fluorescence microscopy, and rested at its basal level in the presence of C3a-desArg, the immediate catabolic product of C3a in vivo. This [Ca2+]i increase could be completely desensitized homologously by C3a as well as inhibited by up to 75% by pertussis toxin. Thus, tumor-derived basophils are suitable for cloning of the human C3a receptor.

Anaphylatoxins↗
PubMed1994

Degranulation from human eosinophils stimulated with C3a and C5a.

It is unclear what actually induces eosinophil degranulation in vivo. We examined eosinophil cationic protein (ECP) release from normal human eosinophils (Eos) in response to C3a and C5a. C3a and C5a induced remarkable ECP release when Eos were preincubated with cytochalasin B. ECP release induced by C3a or C5a was greater than that induced by PAF at a concentration of 10(-7) M. The ED50 for ECP release was 3 x 10(-8) M and 3 x 10(-9) M for C3a and C5a, respectively. C3a or C5a elicited a rapid and transient rise in [Ca2+]i. These results suggest that C3a and C5a may contribute to hypersensitivity diseases by inducing eosinophil degranulation.

Blood Proteins↗
PubMed1991

FUT-175 as a potent inhibitor of C5/C3 convertase activity for production of C5a and C3a.

We examined the inhibitory effect of FUT-175 on the C3/C5 convertase activity of the cobra venom factor-derived enzyme CVF,Bb by measuring C5b6-mediated reactive lysis of unsensitized guinea pig erythrocytes and by measuring directly the released fragments C3-des-Arg and C5a-des-Arg. In this study, we showed that the concentration of 4.5 X 10(-6) M of FUT-175 caused 50% inhibition of C5 convertase activity of CVF,Bb in reactive hemolysis assays, and that 4.0 X 10(-6) M FUT-175 caused 50% inhibition of the production of C3a and C5a generated by the C3/C5 convertase activity of CVF,Bb.

Animals↗
PubMed1997

Evidence that the receptor for C4a is distinct from the C3a receptor.

The cDNAs encoding the human (hC3aR) and mouse C3a receptors (mC3aR) were functionally expressed in RBL-2H3 cells. A calcium mobilization assay was utilized to assess the biologic activity of human anaphylatoxins, and C3a synthetic peptide agonists on hC3aR and mC3aR cells and this activity was compared to the activity of the anaphylatoxins on human neutrophils. Both hC3aR and mC3aR cells responded in a concentration-dependent manner with a robust calcium mobilization response to C3a with 50% effective concentrations (EC50s) of 0.24 nM and 1.3 nM, respectively. The response obtained with hC3aR cells was similar to the response elicited by C3a on human neutrophils (EC50 0.77 nM). The potency of a C3a analogue synthetic peptide (WWGKKYRASKLGLAR), derived from the fifteen carboxy-terminal residues (63-77) of C3a, relative to C3a, in stimulating calcium mobilization differed on cells expressing the human vs. mouse receptors. While the peptide was approximately 10 fold less active than C3a in stimulating calcium mobilization on cells expressing the hC3aR (EC50 2.0 nM), the peptide was essentially equipotent to the native ligand when tested on cells expressing the mC3aR. Data obtained with C4a, purified from activated serum, were difficult to interpret due to possible trace contamination of the C4a with C5a. Subsequently, an alternative C4a isolation scheme was utilized, via cleavage in vitro of purified C4. Concentrations of this latter C4a preparation, of up to 3.3 microM, had no effect on calcium mobilization in human neutrophils or in cells stably expressing the cloned C3a receptors, an indication that C4a does not interact with the C3a receptor.

Amino Acid Sequence↗
PubMed2000

C3a and C5a enhance granulocyte adhesion to endothelial and epithelial cell monolayers: epithelial and endothelial priming is required for C3a-induced eosinophil adhesion.

Effects of the anaphylatoxins C3a and C5a on eosinophil and neutrophil adhesion to HUVEC and to primary culture human bronchial epithelial cells (HBEC) were investigated. Activities on both leukocytes and on structural cells were examined. C3a upregulated beta2 integrin expression and caused shedding of L-selectin on eosinophils, but had no effect on neutrophil adhesion molecule expression. C5a upregulated beta2 integrins and caused shedding of L-selectin on both eosinophils and neutrophils. The potency of C5a was equivalent on both cell types; however, the magnitude of the changes in each of these adhesion molecules was significantly greater in neutrophils than eosinophils. Neither C3a nor C5a altered expression of ICAM-1, VCAM-1, E-selectin or P-selectin on either HUVEC or HBEC. C5a induced adhesion of both neutrophils and eosinophils to unstimulated HUVEC or HBEC, and adhesion was further enhanced when HUVEC and HBEC were "primed" with TNF-alpha and IFN-gamma, respectively. C3a failed to enhance adhesion of either eosinophils or neutrophils to unprimed HUVEC or HBEC, and enhanced only eosinophil adhesion to cytokine-primed HUVEC or HBEC. Similar to C3a, C3a(desArg) and a C3a-analog peptide E7 also enhanced eosinophil adhesion only to cytokine-primed HUVEC and HBEC. These results support the traditional view of anaphylatoxins as leukocyte-specific mediators. The specificity of C3a for eosinophils implicates this molecule as a potential participant in allergic inflammation. The pro-adhesive effects of C3a(desArg) suggest that this molecule, previously characterized as a spasmogenically inactive derivative of C3a, may also alter leukocyte dynamics and migration. Finally, activation of endothelium may represent an important control mechanism for C3a-mediated adhesion preventing unchecked eosinophil adhesion to uninflamed systemic vasculature.

CD18 Antigens↗
PubMed1999

Effect of permeability on indices of haemodialysis membrane biocompatibility.

BACKGROUND: Increases in plasma anaphylatoxins frequently are used as an index of haemodialysis membrane biocompatibility; however, their plasma levels may be influenced by the loss of anaphylatoxins into the dialysate compartment. METHODS: We compared the generation and compartmental distribution of anaphylatoxins, C3a and C5a, in a high flux and a low flux polysulfone membrane dialyser when whole human blood was recirculated through an in vitro haemodialysis circuit. RESULTS: Plasma C3a levels in high flux polysulfone (2.31 +/- 0.81 microg/ml) and low flux polysulfone (3.02 +/- 0.98 microg/ml) dialysers were comparable after 120 min (P = NS). In contrast, dialysate C3a in high flux polysulfone (0.65 +/- 0.31 microg/ml) accounted for 37.5 +/- 7.0% of the total detected (plasma + dialysate) C3a mass in the dialysers, while dialysate C3a in low flux polysulfone dialysers (0.01 +/- 0.01 microg/ml) accounted for only 0.3 +/- 0.3% of the total mass (P < 0.05; high flux vs low flux). Anaphylatoxin C5a was undetectable in the dialysate compartment of either dialyser examined. CONCLUSIONS: Our results indicate that anaphylatoxins readily traverse certain high flux dialysis membranes; consequently, plasma C3a levels may not accurately reflect the C3-activating potential of these membranes.

Biocompatible Materials↗