Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Complement C3a”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed1984

Active site of C3a anaphylatoxin: contributions of the lipophilic and orienting residues.

Activation of the serum complement cascade generates C3a anaphylatoxin, a primary mediator of inflammation. The active-site pentapeptide from the COOH terminus of C3a, Leu-Gly-Leu-Ala-Arg (residues 73-77), exhibits the inflammatory activities and specificity of the native 77-residue polypeptide. Functionally important features of this active site were studied by testing the ability of 22 synthetic analogues of this pentapeptide to contract isolated muscle strips from guinea pig ileum and to desensitize this tissue to contraction induced by human C3a or C5a. The C3a receptors on mast cells and basophils probably contain lipophilic groups that interact with the lipophilic side chains of Leu-73 and Leu-75 and charged groups that interact with the carboxylate and guanidinium groups of Arg-77. The lipophilic contribution of Leu-73 is modest and sterically nonspecific while that of Leu-75 is substantial and sterically specific. Gly-74 and Ala-76 appear to position and orient the adjacent residues Leu-73, Leu-75, and Arg-77 for optimal receptor binding. The contribution of Gly-74 is neither conformationally nor sterically specific while that of Ala-76 is both conformationally and sterically specific. The cellular C3a receptors evidently interact most efficiently with peptides ending in -Leu-Ala-Arg-OH.

Anaphylatoxins↗
PubMed1996

A new biologic role for C3a and C3a desArg: regulation of TNF-alpha and IL-1 beta synthesis.

The complement activation products C3a and C3a desArg are generated in the course of trauma, infection, tissue injury, and ischemia. We have investigated the effects of C3a and C3a desArg on gene expression and protein synthesis of TNF-alpha and IL-1 beta in PBMC. Neither C3a nor C3a desArg alone induced detectable protein or mRNA levels for TNF-alpha and IL-1 beta. C3a modulated LPS-induced TNF-alpha and IL-1 beta synthesis. In nonadherent PBMC, C3a suppressed LPS-induced synthesis of TNF-alpha (20-71% decrease by 0.2-10 microgram/ml of C3a, p less than 0.01) and IL-1 beta (19-57% decrease by 0.5-10 microgram/ml of C3a, p less than 0.01), independently of endogenous production of PGE2. C3a also suppressed LPS-induced mRNA levels for TNF-alpha and IL-1 beta. In contrast, in adherent PBMC, C3a at 5 to 20 microgram/ml enhanced LPS-induced TNF-alpha (75-188% increase, p less than 0.001) and IL-1 beta (119-274% increase, p less than 0.001) synthesis. C3a enhanced TNF-alpha and IL-1 beta mRNA levels in LPS-stimulated adherent cells. Furthermore, C3a desArg shared with C3a the ability to modulate LPS-induced mRNA and protein synthesis for TNF-alpha and IL-1 beta. These results suggest that C3a, thought to be proinflammatory, and C3a desArg, thought to be biologically inactive, are modulators of inflammation. Both C3a and C3a desArg may enhance cytokine synthesis by adherent monocytes at local inflammatory sites, while inhibiting the systemic synthesis of proinflammatory cytokines by circulating cells.

Cell Adhesion↗
PubMed1986

Determination of plasma C3a des Arg levels after blood contact with foreign surfaces.

The products of complement activation, including C3a, C4a, C5a, and their des Arg derivatives, have been used by many investigators as indicators of blood or foreign surface bioincompatibility, e.g., during hemodialysis. One problem encountered is that after extracorporeal circulation over some dialysis membranes very high C3a levels (5,000-10,000 ng/ml) are generated. To the authors' knowledge the only presently available C3a des Arg RIA kit is provided by Upjohn Diagnostics (Kalamazoo, MI, U.S.A.), which covers an assay standard range of 20-500 ng/ml. Since Upjohn's assay procedure manual does not contain a recommended dilution technique the authors undertook a study to determine the best method. The diluents tested include physiologic saline, normal plasma, phosphate-buffered saline-gelatin, and the Upjohn precipitating agent provided in their kit. The results show that only dilution by normal plasma gave reliable results. The use of the other three diluents resulted in an overestimation of C3a levels. Therefore it is important to know the dilution technique used when comparing the results of membrane C3a generating ability presented by different authors. Furthermore, comparison of different membranes where plasma samples in some cases do not require dilution (e.g., polyacrylonitrile membranes) with those requiring dilution (e.g., regenerated cellulose membranes) will lead to distorted results if an accurate technique is not used.

Biocompatible Materials↗
PubMed1985

Involvement of complement in psoriasis and atopic dermatitis--measurement of C3a and C5a, C3, C4 and C1 inactivator.

Normal complement components and activation products were determined in the peripheral blood of 35 patients with atopic dermatitis (AD) and 24 patients with psoriasis at a mild to intermediate stage. None of the patients had received systemic or local steroid therapy 6 weeks prior to blood collection. Levels of C3, C4 and C1 inactivator (C1 INA) were determined in serum by radial immunodiffusion, whereas C3a and C5a levels were measured by radioimmunoassay. In comparison to healthy non-atopic controls, the levels of C3, C4 and C1 INA were found to be significantly increased in both diseases. No substantial differences were detected between patients with psoriasis vulgaris and psoriasis guttata, which suggests that the dissimilarities found were not due to preceding or concomitant infections. In AD, there was a tendency towards increased C3a levels, whereas in psoriasis, C3a levels were significantly increased. In both diseases, no measurable amounts of C5a could be detected. The results indicate that, in both AD and psoriasis, the complement participates in the inflammatory process. Elevated levels of C3a suggest that there is a continuous activation of the complement system leading to the generation of inflammatory mediators.

Adolescent↗
PubMed1981

Complement activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxins.

We observed complement activation in 15 adults undergoing total cardiopulmonary bypass. Plasma levels of C3a were significantly elevated (P < 0.0001) at the beginning of the procedure, and they continued to increase steadily thereafter. At the end of the procedure, C3a levels were more than five times higher than preoperative levels. Plasma levels of C5a (a factor that binds avidly to neutrophils) did not change significantly during cardiopulmonary bypass. Instead, there was significant neutrophilia (P = 0.03) during bypass, and significant transpulmonary neutropenia (P = 0.0002) occurred when cardiopulmonary circulation was reestablished at partial bypass. The neutropenia is consistent with pulmonary-vascular sequestration of C5a-activated granulocytes. We also found that incubation of blood with the nylon-mesh liner of bubble oxygenators, as well as vigorous oxygenation of whole blood, promotes conversion of complement. We conclude that the complement-derived inflammatory mediators C3a and C5a produced during extracorporeal circulation may contribute to the pathogenesis of "post-pump syndromes."

Adult↗
PubMed1996

Expression of high- and low-affinity receptors for C3a on the human mast cell line, HMC-1.

The proteolytic cleavage product of complement component 3, (C3a), is like C4a and C5a, is a potent anaphylatoxin and induces the production of inflammatory mediators in phagocytes. Notably, mast cells respond to C3a with the release of vasoactive substances, including histamine. We have examined the function and receptor binding of C3a in a human leukemic mast cell line, HMC-1. Similar to chemoattractant agonists in leukocytes, C3a induced rapid cytosolic free calcium concentration increases in HMC-1 cells. EGTA did not diminish this response, indicating that mobilizable Ca2+ was from intracellular stores. Receptors of C3a in HMC-1 cells couple in part to Bordetella pertussis toxin-sensitive G-proteins and, therefore, appear to belong to the family of serpentine receptors that require G-proteins for signal transduction. HMC-1 cells express two types of C3a receptors, C3aR1 and C3aR2, that were shown to bind 125I-C3a with high-(Kd1 = 2.1-4.8 nM) or low-affinity (Kd2 = 30-150 nM), and both receptors are expressed at high level: 3 x 10(5)-6 x 10(5) C3aR1/cell and 5 x 10(5)-2.3 x 10(6) C3aR2/cell. Results from cross-linking experiments with 125I-C3a fully agree with the presence of two different classes of C3a receptors in HMC-1 cells. Two membrane proteins with apparent molecular masses of 54-61 kDa (p57) and 86-107 kDa (p97) could be covalently modified with 125I-C3a, and this cross-linking was inhibited with an excess of unlabeled C3a. Many of the known agonists for leukocytes including 13 chemokines (IL-8, NAP-2, GRO alpha, ENA-78, IP10, PF4, MCP-1, 2 and 3, RANTES, MIP-1 alpha, MIP-1 beta and I309), three neuropeptides (neuropeptide Y, somatostatin and calcitonin), as well as C5a, did not activate HMC-1 cells, indicating that C3a is one of a few protein ligands for which this cell line expresses specific receptors. The apparent selectivity for C3a and the abundant expression of C3a receptors make the HMC-1 cell line an excellent choice for the cloning of the receptor genes.

Anaphylatoxins↗
PubMed1987

The role of prostaglandins in C3a-mediated suppression of human in vitro polyclonal antibody responses.

Suppression of polyclonal antibody responses in human peripheral blood mononuclear cell cultures by human C3a appears to involve the release of endogenous prostaglandins from monocytes. C3a was found, under the experimental conditions employed, to activate the cyclooxygenase pathway of arachidonic acid metabolism with the release of large amounts of the prostaglandin E2 species. Suppression of the protein A-induced polyclonal antibody response by C3a is abrogated by the prostaglandin synthesis inhibitor indomethacin. In addition, physiologic amounts of exogenous PGE2 were able to inhibit polyclonal antibody secretion in a manner similar to the suppression observed when C3a was added to culture. These results suggest that C3a-induced release of prostaglandins could be a major element in immunosuppression induced by C3a.

Antibody Formation↗
PubMed1985

Inhibition of cleavage of the third component of human complement (C3) by its small cleavage fragment, C3a: inhibition occurs with the classical-pathway, but not the alternative-pathway, C3 convertase.

Activation of the third component of complement (C), C3, is central to the functioning of the C system in inflammation. Cleavage of C3 by the C3 convertases of both the classical and alternative pathways results in the formation of two split products, C3b and C3a. C3a inhibited cleavage of C3 by the classical-pathway C3 convertase. The inhibition varied in a concn-dependent relationship, with a concn of approximately 40 micrograms/ml yielding 50% inhibition. Removal of the carboxy terminal arginine from the C3a did not alter the inhibition. C3a did not inhibit cleavage of C3 by the alternative C pathway C3 convertase, or cleavage of C5 by C5 convertase. The C3-cleaving capacity of EAC142oxy that had been previously incubated with C3a could be recovered completely by washing the cells, indicating that the C3a binding to the EAC42oxy cell must have been reversed without having had an effect on the amount of C2 bound. Ribonuclease, a molecule of similar size and charge to C3a, did not affect C3 cleavage and C3a inhibition was not reduced by providing a surface for non-specific adsorption of the C3a, suggesting that the effect of C3a on C3 cleavage was not mediated by non-specific interaction with cell surfaces. C3a inhibited the C3-cleaving capacity of the fluid-phase enzyme, C42oxy, to the same degree as it inhibited the cell-bound enzyme, EAC42oxy, indicating that the C3a must interact with the C42 complex directly. Inhibition of C3 cleavage by C3a is the first demonstration of product inhibition of a complement enzyme. It may provide another control of C3 activation.

Arginine↗
PubMed1986

Complement cleavage products in the phototoxic reaction of porphyria cutanea tarda.

We have measured C3, C4, CH50 and complement cleavage products C3a and C5a in in sera and plasma from PCT patients and normal controls 10 min and 1, 4 and 24 h after UVA irradiation. We found elevated C3a concentrations in PCT patients immediately after UVA irradiation and 24 h later. The same was true for CH50, whereas C3, C4 and C5a did not change significantly. No such changes occurred in normal controls. Our data suggest that activation of the complement cleavage product C3a by porphyrin and UV light triggers a series of events that cause tissue damage.

Adult↗
PubMed1982

Modulation of human lymphocyte function by C3a and C3a(70-77).

Human C3a and the synthetic octapeptide C3a (70-77), which retains the activities of an anaphylatoxin, inhibit in a concentration-dependent manner the generation of leukocyte inhibitory factor (LIF) activity by human mononuclear leukocytes and T lymphocytes cultured with the mitogens phytohemagglutinin (PHA) or concanavalin A (Con A) or the antigen streptokinase-streptodornase (SK-SD). The generation of LIF activity was inhibited by 50% by 10(-8) M C3a or C3a(70-77) with PHA or Con A as the stimulus, whereas a more than 10-fold higher concentration of C3a(70-77) than C3a was required to achieve the same level of suppression with SK-SD as the stimulus. Similar concentrations of C3a(70-77) inhibited to the same extent the migration of T lymphocytes stimulated by alpha-thioglycerol of Con A. Neither C3a nor C3a(70-77) altered significantly the uptake of [3H]thymidine by human mononuclear cells exposed to PHA, Con A, or SK-SD. The capacity of C3a(70-77)-Sepharose,m but not Sepharose alone, to adsorb or inactivate mononuclear leukocytes required for the generation of LIF activity established a direct interaction. Analysis of the lymphocytes in the effluent from C3a(70-77)-Sepharose columns, using monoclonal antibodies to surface antigens, showed a selective depletion of the helper/inducer population of lymphocytes. C3a might represent an important mediator of the functionally selective regulation of human T lymphocyte activities by the complement system.

Cell Division↗
PubMed1993

Characterization of C3a anaphylatoxin receptor on guinea-pig macrophages.

We have characterized a C3a receptor on guinea-pig macrophages by 125I-C3a binding and functional responses. Scatchard analysis applied to the 125I-C3a binding to guinea-pig macrophages revealed the existence of two receptor classes; a high-affinity class with approximately 0.63 x 10(5) binding sites/cell with a Kd = 2.7 nM, and a relatively low-affinity class with approximately 1.2 x 10(5) binding sites/cell with a Kd = 51 nM. The binding of C3a to macrophages was totally blocked when there was an excess of C3a. C3a triggered a transient intracellular Ca2+ ([Ca2+]i) mobilization in macrophages, which was accompanied by homologous desensitization. C3a was also capable of generating O2- from macrophages. The C3a-induced Ca2+ response and O2- generation were not detected in the pertussis toxin-treated macrophages, suggesting that G proteins are coupled with the C3a receptors of macrophages. Although the C3a-induced O2- generation was inhibited by staurosporine, it was more resistant to staurosporine than phorbol 12-myristate-13-acetate (PMA)-induced O2- generation, suggesting that a protein kinase distinct from protein kinase C may be associated with the C3a receptor.

Animals↗
PubMed1996

Role of atheroma liposomes and malondialdehyde-modified low-density lipoproteins in complement activation.

We investigated the ability of atheroma-associated liposomes and malondialdehyde (MDA)-modified low-density lipoproteins (MDA-LDL) to activate complement. Complement activation markers C3a, Bb, C4d and SC5b-9 were measured in both normal and complement-deficient sera. We found that MDA-LDL was able to generate C3a and SC5b-9, predominantly by the alternative pathway. High-density lipoproteins modified with MDA were also capable of C3a generation although to a lesser degree. The presence of atheroma-associated liposomes did not result in detectable levels of complement activation markers. We conclude that MDA-modified lipoproteins may represent a possible source for complement activation within atherosclerotic lesions.

Aortic Diseases↗
PubMed1993

Proteins separated from human IgG molecules.

Immunoglobulin G binding proteins were separated from human IgG molecules using 1 N acetic acid followed by 5 M guanidinium chloride in 0.1 M acetic acid. The proteins thus obtained were heterogeneous as demonstrated by SDS-PAGE and reverse-phase HPLC. The isolated proteins consisted of two types: the C3a and C4a complement fragments (anaphylatoxins) and immunoglobulin peptide chain fragments V kappa I and C gamma 3. Both anaphylatoxins immobilized on cellulose nitrate membranes could reassociate with intact IgG molecules. The ubiquitous presence of C3a in IgG preparations was demonstrated using monoclonal antibodies specific for C3a. Nearly all of the bound anaphylatoxin molecules were found in the Fab fragment. These findings suggest that IgG molecules can eliminate anaphylatoxins from the circulation, and thus prevent harmful effects due to these active complement components.

Amino Acid Sequence↗
PubMed1991

Biocompatibility of four plasmapheresis membranes in patients treated for hypercholesterolemia.

Membrane plasma separation uses artificial polymers which might interact with blood components during treatment. In 7 patients treated for familial hypercholesterolemia with heparin-induced extracorporeal LDL precipitation (HELP), we studied 4 different synthetic plasma separation materials. The effect of membranes made from polyethylene, polymethylmethacrylate (PMMA), polypropylene and polysulfone on complement activation (C3a), granulocyte elastase release and granulocyte count were measured repeatedly during the treatment. Polyethylene and PMMA induced high levels of plasma elastase and marked granulocytopenia after 60 min of treatment, much later than during hemodialysis, where granulocyte nadir is known to occur already after 15 min. Polysulfone and polypropylene did not change granulocyte counts and caused only modest levels of elastase during plasmapheresis. Complement activation was present in all 4 membranes but with polyethylene, very high concentrations of C3a were detected. These data indicate that irritation of immune system components as granulocytes or the complement system do occur during plasmapheresis to different degrees depending on the membrane material used. Reinfusion of plasma after processing increases the amount of plasmatic activation products infused into the patient. This was the case, although the plasma processing procedure itself did not add activation products to the plasma. Activation patterns during plasma separation differ from those known to occur during hemodialysis despite use of the same polymer. Immunocompromised patients treated with plasmapheresis may react differently than these otherwise healthy subjects with familial hypercholesterolemia.

Biocompatible Materials↗
PubMed1990

Biocompatibility of blood tubings.

We studied hemocompatibility of various blood tubings with C3a anaphylatoxin measurement and comparative electron scanning microscopy. The following tubing materials were tested: polyvinylchloride (PVC) plasticised with phthalate (PVC), pvc plasticised with phthalate coextruded with polyurethane (PIV), and two phthalate-free lines: pvc plasticised with trimellitate coextruded with polyurethane (TRI) and pvc plasticised with LT 360 (LTP). Results of C3a generation rate showed a significant activation by all blood tubings, with a reduced rate with PIV when compared to all others. Electron scanning microscopy showed marked alterations of PIV surface on tubings stored for 6 months. Protein deposits on internal surfaces after dialysis were similar whatever tubing material was tested, but adhesive cell number was greater with TRI when compared to PVC and LTP. Hemocompatibility is unchanged with phthalate-free tubings when compared to phthalate plasticised ones. In contrast with phthalate plasticised PVC there is no beneficial effect of polyurethane coextrusion with trimellitate plasticised PVC in regard to C3a generation.

Anaphylatoxins↗
PubMed1996

Complement activation by a B cell superantigen.

Staphylococcal protein A (SpA), acting as a B cell superantigen, binds to the Fab region of human VH3+ Igs. Using SpA abrogated of its IgG Fc binding activity (Mod SpA) as a model B cell superantigen, we determined whether such an interaction causes complement activation. Addition of Mod SpA to human serum led to complement consumption and the generation of C3a. To determine whether this complement activation 1) was due to an interaction between VH3+ Igs and the Fab binding site of SpA and 2) proceeded via the classical complement pathway, we tested a panel of monoclonal IgM proteins for the ability to hind C1q following interaction with SpA. C1q binding was restricted to SpA-reactive, VH3+ IgM proteins. To formally determine whether the binding of SpA to the reactive VH3+ IgM proteins led to complement activation, we reconstituted the serum from a hypogammaglobulinemic patient with monoclonal IgM proteins and measured complement consumption and C3a generation following the addition of Mod SpA. We observed complement consumption and C3a production only in Mod SpA-treated serum reconstituted with a VH3+, SpA-binding, IgM protein. Taken together, these results provide compelling evidence that the interaction of the Fab binding site of SpA and VH3+ Igs can lead to complement activation via the classical pathway. This novel interaction may have significant implications for the in vivo properties of a B cell superantigen.

Adult↗