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PubMed2006

Multifunctional glyceraldehyde-3-phosphate dehydrogenase of Streptococcus pyogenes is essential for evasion from neutrophils.

Streptococcus pyogenes is an important pathogen that causes pharyngitis, sepsis, and rheumatic fever. Cell-associated streptococcal C5a peptidase (ScpA) protects S. pyogenes from phagocytosis and has been suggested to interrupt host defenses by enzymatically cleaving complement C5a, a major factor in the accumulation of neutrophils at sites of infection. How S. pyogenes recognizes and binds to C5a, however, is unclear. We detected a C5a-binding protein in 8 M urea extracts of S. pyogenes by ligand blotting using biotinylated C5a. Searching of genome databases showed that the C5a-binding protein is identical to the streptococcal plasmin receptor (Plr), also known as streptococcal surface dehydrogenase (SDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In the present study we identified a novel function of this multifunctional protein. Western blotting and immunofluorescence microscopy with anti-Plr/SDH/GAPDH showed that Plr/SDH/GAPDH is located on the bacterial surface and released into the culture supernatant. Next, we examined whether the streptococcal Plr/SDH/GAPDH inhibits the biological effects of C5a on human neutrophils. We found that soluble Plr/SDH/GAPDH inhibits C5a-activated chemotaxis and H2O2 production. Furthermore, our results suggested that soluble Plr/SDH/GAPDH captures C5a, inhibiting its chemotactic function. Also, cell-associated Plr/SDH/GAPDH and ScpA were both necessary for the cleavage of C5a on the bacterial surface. Together, these results indicate that the multifunctional protein Plr/SDH/GAPDH has additional functions that help S. pyogenes escape detection by the host immune system.

Animals↗
PubMed1993

Gene expression of interleukin-1 beta during hemodialysis.

It is still controversial whether the hemodialysis (HD) procedure is an inflammatory process in vivo. Therefore, we studied the gene expression of interleukin-1 beta (IL-1 beta) as a marker of inflammation in peripheral blood mononuclear cells (PBMC) of patients during HD by Northern blotting and polymerase chain reaction. Compared to PBMC separated pre-HD (1.0 densitometric units), the amount of IL-1 beta mRNA was increased in PBMC leaving the dialyzer (12.2 +/- 2 densitometric units, P < 0.01), but was not increased in PBMC re-entering the dialyzer from the systemic circulation (0.6 +/- 0.1 densitometric units) in all 12 patients studied. The maximal amount of IL-1 beta mRNA in PBMC was seen at five minutes after start of HD. There was a significant correlation between the increase in IL-1 beta mRNA and the increase in activated complement C5a (r = 0.71, P < 0.01). HD using less complement-activating membranes (hemophan, polysulfone, polyamide or polyacrylonitrile) resulted in no detectable IL-1 beta mRNA. Furthermore, a monoclonal antibody against human C5a reduced the increase in IL-1 beta mRNA by 83% (P < 0.05), indicating that C5a plays a major role for induction of IL-1 beta mRNA during HD. This study demonstrates that during HD with regenerated cellulose, gene expression for IL-1 beta takes place in PBMC.

Base Sequence↗
PubMed2006

Human plasmacytoid dendritic cells express receptors for anaphylatoxins C3a and C5a and are chemoattracted to C3a and C5a.

The presence of plasmacytoid dendritic cells (pDC) was recently demonstrated in lesions of inflammatory skin diseases. Since anaphylatoxins or their precursors were also found in such lesions, we investigated a possible interaction between pDC and anaphylatoxins C3a and C5a. pDC precursors isolated from peripheral blood did not express the receptors for C3a and C5a, complement C3a receptor (C3aR) and complement C3a receptor (C5aR). If these pDC precursors were cultured with IL-3, the resultant immature pDC expressed both receptors. Expression of C3aR and C5aR could also be demonstrated on pDC in lesions of cutaneous lupus erythematosus and allergic contact dermatitis. Such pDC were immature since they lacked the expression of the maturation marker CD83. Blood-derived pDC matured with CpG oligonucleotides downregulated the receptors. Immature pDC responded to C3a and C5a (but not C3adesArg) stimulation with increased F-actin polymerization and chemotactic migration. In contrast, interferon alpha production, surface molecule expression, and T-cell stimulatory capacity were not significantly modulated by C3a or C5a. Thus, immature pDC represent another type of antigen-presenting cell that express C3aR and C5aR, and respond to anaphylatoxins with chemotaxis. This might be relevant in the direction of pDC to cutaneous lesions of inflammation, for example, in lupus erythematosus or contact dermatitis.

Anaphylatoxins↗
PubMed1995

Structure, function and cellular expression of complement anaphylatoxin receptors.

The past year has seen significant advances in determining the important structural-functional domains of the complement C5a anaphylatoxin receptor. The current model suggests a two-site binding motif in which part of the amino-terminal extracellular domain of the receptor is recognized first by the amino-terminal end and disulfide-linked core of the C5a ligand. This is followed by interaction of the carboxy-terminal end of C5a with a second, and as yet undefined, site on the receptor that results in activating appropriate signal transduction pathways via receptor coupled G proteins. Another recent advance has been the discovery that the C5a receptor is expressed on non-myeloid cells, suggesting that C5a confers previously unexpected functions on certain target tissue cells, including bronchial and alveolar epithelial cells, hepatocytes, astrocytes, and vascular endothelial cells.

Amino Acid Sequence↗
PubMed1984

Characterization of the anaphylatoxin inactivator and chemotactic factor inactivator activities during cardiopulmonary bypass.

Complement activation productive of phlogistic products has been suggested as one of the major mechanisms of the pump lung syndrome associated with cardiopulmonary bypass (CPB) surgery. Recent studies have demonstrated the presence of circulating C3a antigens in the serum of patients undergoing CPB and have suggested that the vasoactive nature of C3a may contribute directly to the interstitial edema and vascular changes seen in pump lung syndrome. In an effort to unravel the underlying mechanisms of pump lung syndrome, we undertook investigations to determine whether CPB and associated complement activation would alter the serum levels of the major regulators of both C3a and C5a complement split products. These serum regulators designated chemotactic factor inactivator (CFI) and anaphylatoxin inactivator (AI) were measured in the serum of patients undergoing CPB. In these studies, we demonstrated that during CPB a rapid and dramatic drop in the anaphylatoxin inactivator activities occurred within the first 10 minutes of CPB. These lowered AI levels were maintained throughout the CPB but AI levels returned to normal within 24 hours postsurgery. CFI levels were generally maintained throughout the CPB surgery with only minimal depressions in CFI levels during or after CPB surgery. These studies clearly demonstrate that the major regulator system of the complement-derived vasopermeability factors (C3a and C5a) is dramatically depressed during cardiopulmonary bypass and may suggest that the mechanisms of interstitial edema associated with pump lung syndrome may at least, in part, be related to the loss of the serum regulator enzyme carboxypeptidase N, also designated AI.

Anaphylatoxins↗
PubMedDate not supplied

Bovine milk fat globules do not inhibit C5a chemotactic activity.

The C5a complement fragment is a potent inflammatory molecule but its contribution to the inflammatory response of the mammary gland remains uncertain. One of the unresolved questions is the possible interference of whole milk with C5a. In this study, the chemotactic activity ofpurifled bovine C5a was tested in the presence of whole or skimmed milk. Milk from healthy glands acted as a chemoattractant, which could mask any inhibitory effect on C5a activity. To circumvent milk activity, washed milk fat globules were incubated with optimal (1 nM) or suboptimal (0.1 nM) concentrations of C5a, and the eventual chemoattractant activity was measured. There was no reduction in C5a-induced migration through a polycarbonate filter or shape-change of neutrophils. The concentrations of C5a determined by ELISA in the fluid phase were not reduced after incubation with the fat globules. It can be concluded that bovine milk fat globules do not trap or degrade C5a. Although these results do not explain the inhibitory effect of whole milk in the C5a-induced recruitment of neutrophils in milk, they suggest that milk does not inhibit the second major activity of C5a (apart from chemotaxis), i.e. the stimulation of phagocytic and bactericidal activities of neutrophils.

Animals↗
PubMed1988

Endotoxemia and neutrophil activation in vivo.

There is a growing body of data to suggest that marginated granulocytes mediate much of the pulmonary damage observed during endotoxemia. The mechanism(s) by which endotoxemia initiates neutrophil margination and cytotoxicity remain either controversial or unknown. The objectives of this study were 1) to determine the temporal relationship between endotoxin-induced decreases in mean arterial pressure and circulating neutrophils, 2) to monitor neutrophil activation in vivo by measuring myeloperoxidase (MPO) activity in the plasma and lymph, and 3) to assess the interaction between endotoxin and complement in activation of neutrophilic oxidative metabolism in vitro. We found that a bolus injection of endotoxin causes a concurrent decrease in both mean arterial pressure and circulating neutrophils at 2 min postinfusion. Blood pressure recovered to approximately 70% of control values by 180 min, whereas circulating neutrophils remain depressed at 20% of control values for the entire experimental period. Using MPO as a marker for neutrophil activation, we found that infusion of endotoxin produces a dramatic increase in plasma and lymph MPO activity, suggesting activation of neutrophilic metabolism in vivo. In vitro data showed that both endotoxin and plasma were required for optimal neutrophilic degranulation and superoxide formation. We conclude that 1) the appearance of MPO in the plasma (or lymph) may be a useful neutrophil marker for neutrophil activation in vivo and may prove useful in following the course of neutrophil-mediated tissue injury during endotoxemia, and 2) endotoxin-activated complement (C5a) activates neutrophils to produce cytotoxic oxidants.

Animals↗
PubMed1994

Inhibition of C5a des Arg-induced neutrophil alveolitis in transgenic mice expressing C-reactive protein.

C-reactive protein (CRP) is the classic acute phase reactant in man with serum levels elevated up to 1,000-fold after the onset of inflammation. CRP inhibits chemotaxis of complement (C5a)-stimulated neutrophils in vitro and rabbits with elevated serum CRP levels exhibit diminished neutrophil infiltration and vascular permeability in a model of C5a-induced alveolitis. To specifically evaluate the effect of CRP on C5a-induced neutrophil inflammation in vivo, experiments were performed in transgenic mice capable of expressing rabbit CRP in an inducible fashion. After direct instillation of a known inflammatory agent (C5a des Arg) into the airways, transgenic mice with high plasma levels of CRP showed significantly diminished infiltration of neutrophils into bronchoalveolar lavage fluid (BALF) and a significant reduction of BALF total protein levels compared with normal mice. These data indicate that CRP can diminish lung injury by a reduction in neutrophil influx and protein leakage into alveoli following complement-induced inflammation.

Animals↗
PubMed1991

Differential inhibition and potentiation by cell-permeant analogues of cyclic AMP and cyclic GMP and NO-containing compounds of exocytosis in human neutrophils.

The chemoattractants, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe), complement C5a and platelet-activating factor (PAF), induce beta-glucuronidase release and aggregation and an increase in cytosolic Ca2+ [Ca2+]i in human neutrophils. We studied the roles of cAMP and cGMP in neutrophil avtivation, using their cell-permeant analogues, N6,2'-O-dibutyryl adenosine 3':5'-cyclic monophosphate (Bt2cAMP) and N2,2'-O-dibutyryl guanosine 3':5'-cyclic monophosphate (Bt2cGMP) and the NO-containing compounds, sodium nitroprusside (SNP), 3-morpholino-sydnonimine (SIN-1) and its prodrug, molsidomine (SIN-10). Bt2cAMP, Bt2cGMP, SIN-1 and SIN-10 but not SNP inhibited exocytosis induced by fMet-Leu-Phe. Superoxide dismutase potentiated the inhibitory effect of SIN-1. Bt2cGMP and SNP potentiated C5a-induced beta-glucuronidase release, Bt2cAMP, KCN, SIN-1 and SIN-10 being ineffective. KCN partially reversed the stimulatory effect of SNP, and in the presence of superoxide dismutase, SIN-1 potentiated C5a-induced exocytosis. PAF-induced beta-glucuronidase release was not affected by Bt2cAMP, Bt2cGMP, SNP and SIN-1. Bt2cGMP was more effective than Bt2cAMP to inhibit aggregation and the increase in [Ca2+]i induced by fMet-Leu-Phe at submaximally effective concentrations. C5a-induced rises in [Ca2+]i were not affected by Bt2cAMP and Bt2cGMP. Bt2cAMP but not Bt2cGMP inhibited the effect of PAF at submaximally effective concentrations on [Ca2+]i. Our data suggest (I) that Bt2cGMP and Bt2cAMP differentially modulate neutrophil activation, that (II) NO-containing compounds partially mimic the effects of Bt2cGMP on exocytosis and that (III) cGMP plays an inhibitory role in fMet-Leu-Phe- and a stimulatory role in C5a-induced beta-glucuronidase release.

1-Methyl-3-isobutylxanthine↗
PubMed1989

[Experimental research on the pathogenic mechanisms in adult respiratory distress syndrome].

In order to study the pathogenic mechanisms of adult respiratory distress syndrome (ARDS), the neutrophil aggregation activity, platelet aggregation rate and levels of thromboxane, prostacyclin, superoxide dismutase, lipoperoxides, neutrophil elastase, alpha 1-antitrypsin and angiotensin conversion enzyme were measured in 84 experimental dogs. Under the action of activated complement C5a, polymorphonuclear leukocyte aggregation with increased release of oxygen radicals play an important role in the pathogenesis of ARDS.

Animals↗
PubMed2007

Effect of biopassive and bioactive surface-coatings on the hemocompatibility of membrane oxygenators.

Postoperative complications associated with cardiopulmonary bypass (CPB) surgery and extracorporeal circulation (ECC) procedures are still a major clinical issue. Improving the hemocompatibility of blood contacting devices used for ECC procedures may ameliorate various postpump syndromes. In a simulated CPB model using human blood, we investigated the hemocompatibility, fibrinogen adsorption, and platelet receptor (GPIIb-IIIa) binding capacity of surface-modified membrane oxygenators (Jostra Quadrox). Three groups were compared: (i) biopassive protein coatings (SafeLine), (ii) bioactive heparin coatings (BioLine), and (iii) noncoated controls. During the 2 h recirculation period, plasma concentrations of activation markers for platelets (beta-thromboglobulin), inflammation (elastase), complement (C5a), and coagulation (prothrombin fragment 1+2, thrombin-antithrombin III) were lower in the groups with biopassive and bioactive coatings compared to the noncoated group (p < 0.01). These parameters did not significantly differ between the two surface-coated groups, except for complement activation: C5a levels were higher in the biopassive group compared to the bioactive group (p < 0.01). Moreover, surface-coated oxygenators showed less fibrinogen adsorption, GPIIb-IIIa binding, and platelet/leukocyte adhesion (p < 0.01). We assume that fewer fibrinogen and platelet receptor molecules bound to the surface-coated oxygenator surfaces results in fewer platelet adhesion and activation, which will significantly contribute to the improved hemocompatibility of the biopassive and bioactive oxygenators. Our results suggest that the application of bioactive oxygenators (BioLine) during CPB surgery may reduce postoperative complications for the patient more effectively than biopassive oxygenators (SafeLine).

Adsorption↗
PubMed2004

Stat3 activation in acute lung injury.

Stat3 plays diverse roles in biological processes including cell proliferation, survival, apoptosis, and inflammation. Very little is known regarding its activation and function in the lung during acute inflammation. We now show that Stat3 activation was triggered in lungs and in alveolar macrophages after intrapulmonary deposition of IgG immune complexes in rats. Low levels of constitutive Stat3 were observed in normal rat lungs as determined by the EMSA. Stat3 activity in whole lung extracts increased 2 h after initiation of IgG immune complex deposition, reaching maximal levels by 4 h, whereas Stat3 activation was found in alveolar macrophages as early as 30 min after onset of injury. Expression and activation of Stat3 mRNA, protein, and protein phosphorylation was accompanied by increased gene expression of IL-6, IL-10, and suppressor of cytokine signaling-3 in whole lung tissues. Both Tyr(705) and Ser(727) phosphorylation were involved in Stat3 activation as assessed in whole lung extracts. C5a (complement 5, fragment a) per se can induce phosphorylation of Ser(727) of Stat3. In vivo, Stat3 activation was dramatically suppressed by depletion of neutrophils or lung macrophages, resulting in reduced gene expression of IL-6 and IL-10 in whole lung tissues. Using blocking Abs to IL-6, IL-10, and C5a, Stat3 activation induced by IgG immune complexes was markedly diminished. These data suggest in the lung injury model used that activation of Stat3 in lungs is macrophage dependent and neutrophil dependent. IL-6, IL-10, and C5a contribute to Stat3 activation in inflamed rat lung.

Animals↗
PubMed1996

Cell culture system for studying bovine neutrophil diapedesis.

Neutrophils are the major defense against bacterial infection in the bovine mammary gland. Neutrophils migrate from blood into the lumen of the gland in response to inflammatory stimuli. This study describes the development of a system of cell culture that can be used to study neutrophil diapedesis through secretory and ductal mammary epithelial barriers. The culture system consists of successive layers of collagen, fibroblasts, collagen, and a confluent monolayer of secretory or ductal epithelial cells layered on a porous membrane. Confluence was determined by electrical resistance and trypan blue diffusion. Neutrophil diapedesis occurred from the basal to the apical surface of the monolayers. Purified complement C5a, fetal bovine serum that had been activated by zymosan, and fetal bovine serum that had been activated by Escherichia coli induced neutrophil diapedesis. Neutrophil diapedesis was greater across ductal cell monolayers. Blood neutrophils from five cows differed in their ability to migrate through the multilayered culture system in response to C5a. Monoclonal antibodies to C5a blocked diapedesis induced by purified C5a but had no effect on diapedesis induced by fetal bovine serum that had been activated by zymosan or by fetal bovine serum that had been activated by E. coli endotoxin, indicating that factors other than C5a were chemotactic for neutrophils. Monomeric IgG2, immune complexes, and E. coli endotoxin did not induce neutrophil diapedesis.

Animals↗
PubMed1999

Cellulose carbamates and derivatives as hemocompatible membrane materials for hemodialysis.

Dialysis membranes made from regenerated cellulose are under dispute because of their alleged lack of hemocompatibility. The introduction of membranes from synthetically modified cellulose, like cellulose acetate or Hemophan, has proven, however, that hemocompatible membranes can be fabricated from cellulose by means of chemical surface modifications. In addition to membranes made from modified cellulose like ethers or esters, which were investigated in earlier experiments, we looked for further cellulose modifications to be assessed for their hemocompatibility. For this purpose, we synthesized a series of cellulose carbamate derivatives to profit from the excellent hemocompatibility pattern of the urethane family. In vitro investigations on membranes made from these cellulose modifications proved a direct relationship between the degree of modification and hemocompatibility. This was proven for the following 3 representative hemocompatibility parameters: complement C5a generation, thrombin-antithrombin (TAT) III formation, and platelet count (PC). As already shown for modifications made from cellulose esters, a direct dependency between improved hemocompatibility and the degree of substitution (DS) in the cellulose molecule could be found. In our experiments, a degree of substitution below a value of 0.1 led to a nearly complete suppression of complement activation for all cellulose carbamates under investigation. In contrast to data on cellulose esters, we observed that molecular weight or molecular conformation of chemical substituents exerted only a minor effect on the hemocompatibility pattern. In addition, data on cellulose carbamate esters (e.g., cellulose succinate-phenyl-carbamate) show that a simultaneous but balanced substitution with hydrophilic and hydrophobic groups at the surface of the cellulose polymer is a further prerequisite for optimal hemocompatibility. It seems that the carbamate configuration per se has a positive effect on the hemocompatibility pattern of synthetically modified cellulose membranes.

Antithrombin III↗
PubMed2005

Effects of calcineurin inhibitors on an in vitro assay for chronic urticaria.

BACKGROUND: Chronic urticaria is a common skin disorder, which causes considerable morbidity. In approximately 40% of cases, patients have an autoimmune disorder in which functional antibodies cause degranulation of mast cells and basophils, and C5a complement augments this in varying amounts from patient to patient. Since the calcineurin inhibitor ciclosporin has been used in chronic autoimmune urticaria, we examined the effect of ciclosporin and other drugs on the release of histamine from basophils when stimulated by sera from patients with chronic autoimmune urticaria. METHODS: Leucocytes from healthy donors were isolated and incubated in varying concentrations of ciclosporin, ascomycin, methotrexate, diphenhydramine or hydroxyzine for 30 min prior to stimulation with serum from urticaria patients known to have functional immunoglobulin (Ig)G antibodies directed against the alpha subunit of the IgE receptor. Histamine release was then measured. RESULTS: Pre-incubating cells with ciclosporin and ascomycin produced dose-dependent inhibition of histamine release when cells were stimulated by sera of urticaria patients, by purified IgG from these sera, but not by C5a. Inhibition was not prevented by C5a receptor blocking antibodies. No inhibition was seen with methotrexate, diphenhydramine or hydroxyzine. CONCLUSIONS: This is the first demonstration of inhibition of histamine release by calcineurin inhibitors employing sera of patients with chronic autoimmune urticaria. These drugs may work by interfering with intracellular signalling in cells following cross-linking of the IgE receptor, but not following stimulation of the C5a receptor.

Basophils↗
PubMed1995

Induction of eosinophil cytokine generation by chemoattractants.

Recent studies have shown that eosinophils are capable of generating and releasing cytokines, illustrating a novel biologic aspect of eosinophils in regulating allergic inflammation by either autocrine or paracrine mechanisms. The effect of chemotactic agonists on eosinophil cytokine generation was examined by determination of interleukin-8 (IL-8) as a main parameter. Both complement C5a and N-formyl-methionyl-leucyl-phenylalanine (FMLP) stimulated eosinophils to release IL-8, but platelet activating factor (PAF) did not exert any significant effects. The generation of IL-8 by chemoattractants was absolutely dependent on the presence of cytochalasin B. Pertussis toxin completely attenuated C5a- and FMLP-induced IL-8 production, indicating the involvement of pertussis toxin-sensitive G proteins in the signal transduction process. In situ hybridization showed that both C5a and FMLP promoted eosinophil IL-8 production via transcriptional gene activation. Furthermore, C5a and FMLP, but not PAF, induced significant secretion of granulocyte-macrophage colony-stimulating factor from eosinophils. These results indicate that C5a and FMLP stimulate eosinophils to elaborate cytokines, which could be an important mechanism in the regulation of allergic inflammation.

Actin Cytoskeleton↗