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PubMed1984

LPS stimulation of complement (C3) synthesis by a human monocyte cell line.

The human monocyte-like cell line, U937, was utilized as a model system to assess the influence of lipopolysaccharides (LPS) from Escherichia coli and other immunomodulatory agents on the biosynthesis of complement component C3 by monocytoid cells. The amount of C3 accumulated in the medium of cultured cells was measured by an enzyme-linked immunoabsorbent assay (ELISA). In the presence of LPS (0.01 and 0.10 microgram/ml) C3 production by U937 cells was increased by 2- and 5-fold, respectively. C3 production was also increased in the presence of lymphokine-containing supernatants obtained from human peripheral blood mononuclear cells after their stimulation with concanavalin A-sepharose. Human gamma-interferon (50-500 units/ml) stimulated C3 production by U937 cells. Stimulation of C3 production by LPS or mononuclear cell supernatants was blocked by cycloheximide. LPS (0.10 and 1.0 microgram/ml) also stimulated PGE2 production by U937 cells but failed to increase PGE2 at the lowest concentration (0.01 micrograms/ml) shown to increase C3 biosynthesis. Although exogenous PGE1 (10(-7) and 10(-6) M) promoted a small increase in C3 production, the effect of LPS was not decreased by a concentration of indomethacin (10(-6) M) that inhibited biosynthesis of PGE2. Therefore, LPS-induced C3 synthesis is not mediated by an increase in PGE2 in U937 cells. In summary, these observations suggest that C3 biosynthesis by monocytes/macrophages can be modulated by mediators of cellular immune responses found in the microenvironment of a localized inflammatory reaction.

Alprostadil↗
PubMed1989

An affinity for complement C3 as a possible reason for the potency of naturally occurring antibodies in mediating tissue homeostasis.

Certain naturally occurring antibodies stimulate alternative complement pathway C3b deposition. We propose that only those IgG antibodies stimulate alternative complement pathway which have an affinity for C3. Their weak binding to C3 in plasma increases the probability that covalently linked C3b-IgG complexes are formed during C3 activation. Such complexes are known to be much more efficient than C3b in mediating positive feedback of C3 activation, since they are more stable against inactivation by factor I and H. The hypothesis is supported by functional properties of naturally occurring antibodies to erythrocyte band 3 protein. Their ability to stimulate alternative complement pathway C3b deposition increases the potency of these low titer antibodies as opsonins.

Antigen-Antibody Complex↗
PubMed1978

IgA and C3 complement in the uninvolved skin in dermatitis herpetiformis after gluten withdrawal.

IgA deposits in the skin in 53 patients with dermatitis herpetiformis (DH) have been studied in relation to treatment. In 19 patients the disorder was controlled by a gluten-freen diet (GFD) alone, in 13 patients by dapsone and GFD and in 18 by dapsone alone. In 3 patients the skin disorder became insignificant and required no treatment. Of the patients taking a GFD alone, six had been clear of skin lesions for 7 years, 5 for 3--5 years, and 8 for periods of 6 months--3 years. IgA deposits were found in all patients in an initial biopsy in a second biopsy after treatment for periods varying from 1 to 7 years. There was no difference in the quantity of IgA, as assessed by the amount of fluorescence, whether patients were controlled with a GFD alone, GFD and dapsone, dapsone alone, or in those in clinical remission. The C3 component of complement was present in the skin in 3 of the 19 patients (16%) controlled by a GFD alone, 6 of the 13 patients (46%) of those controlled by a GFD and dapsone, and in 12 of 18 (66%) of the patients taking dapsone alone, and in one of the patients in clinical remission.

Adult↗
PubMed1994

The structure of an alternate form of complement C3 that displays costimulatory growth factor activity for B lymphocytes.

In this study, the structure of a novel 1.9-kb transcript coding for complement component 3 (C3) is described. This alternate C3 is identical to the 3' end of the C3 message beginning at position 3300 of the C3 cDNA. Its transcription appears to be driven by an alternate promoter located within intron 8 of the C3 gene. This alternate C3 message contains an open reading frame that may encode a 536-amino acid-long protein identical to the 3' part of the C3 alpha chain. The resulting protein contains the complement receptor CR2 binding site. The suggested 5' end of coding region of the alternate C3 includes information for a potential hydrophobic leader peptide that would allow secretion of the protein. In vitro assays with macrophage-depleted mouse splenic B cells indicate that an activity is secreted from cell lines transfected with the alternate C3 cDNA. Together with Sepharose-bound immunoglobulin M-specific monoclonal antibodies and interleukin 2, it costimulates the proliferation of B cells. Implications for possible in vivo functions are discussed.

Alternative Splicing↗
PubMed2004

Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist.

The role of complement components in traumatic brain injury is poorly understood. Here we show that secondary damage after acute cryoinjury is significantly reduced in C3-/- or C5-/- mice or in mice treated with C5a receptor antagonist peptides. Injury sizes and neutrophil extravasation were compared. While neutrophil density increased following traumatic brain injury in wild type (C57BL/6) mice, C3-deficient mice demonstrated lower neutrophil extravasation and injury sizes in the brain. RNase protection assay indicated that C3 contributes to the induction of brain inflammatory mediators, MIF, RANTES (CCL5) and MCP-1 (CCL2). Intracranial C3 injection induced neutrophil extravasation in injured brains of C3-/- mice suggesting locally produced C3 is important in brain inflammation. We show that neutrophil extravasation is significantly reduced in both C5-/- mice and C5a receptor antagonist treated cryoinjured mice suggesting that one of the possible mechanisms of C3 effect on neutrophil extravasation is mediated via downstream complement activation products such as C5a. Our data indicates that complement inhibitors may ameliorate traumatic brain injury.

Animals↗
PubMed1984

Defective binding of the third component of complement (C3) to Streptococcus pneumoniae in multiple myeloma.

Patients with multiple myeloma (MM) are at an increased risk for infections with bacteria that require opsonization with complement. Because Streptococcus pneumoniae is the most frequently encountered pathogen in these patients, we investigated the ability of serum from patients with MM to mediate the binding of C3b, the major opsonin of the complement system, to S. pneumoniae. S. pneumoniae types 3, 14, and 25 were chosen for study, since S. pneumoniae type 3 activates primarily the classical complement pathway (CCP), type 25 primarily the alternative complement pathway (ACP), and type 14 both pathways. S. pneumoniae were treated with normal serum or serum from 17 patients with MM, and the bound C3b was quantified with fluorescein-conjugated anti-C3 in a spectrophotofluorometric assay. Despite normal or elevated serum concentrations of C3, total hemolytic complement, and C-reactive protein in all of the MM sera, factor B in 16/17 such sera, and C4 in 14/17 MM sera studied, all 17 sera demonstrated a defect in C3b binding to type 3 (32.7% +/- 6% of normal). In addition, serum from 15/17 patients bound decreased amounts of C3b to types 14 (39.6% +/- 8%) and 25 (52.2% +/- 8%). Mixing normal serum with MM serum restored MM C3b binding activity to all three S. pneumoniae types, suggesting that the defect was related to a deficiency rather than an inhibitor of C3 activation. Although MM patients are unable to produce specific antibodies to bacterial antigens, the addition of anti-S. pneumoniae antibodies to MM serum did not enhance C3b binding to any of the S. pneumoniae types. However, when S. pneumoniae were opsonized in a mixture of MM serum and C3-depleted normal serum, C3b binding was restored to all three S. pneumoniae types, demonstrating that MM C3 functions normally in the presence of other normal serum factors. In the present studies, the MM C3b binding defect appeared to correlate with the incidence of S. pneumoniae infections. Serum from patients with a history of an S. pneumoniae infection bound significantly less C3 (20.5% +/- 4%) than those study patients without a history of an S. pneumoniae infection (55.8% +/- 8%) (p less than 0.0025). Thus, MM serum has a defect in the activation of C3, and this may contribute to the increased susceptibility of MM patients to S. pneumoniae infections.

Complement C3↗
PubMed1980

Transferrin, C3 complement, haptoglobin, plasminogen and alpha 2-microglobulin in patients with urogenital tumors.

The serum levels of transferrin, haptoglobin, C3 proactivator, plasminogen and alpha 2-macroglobulin have been measured in patients suffering from urogenital cancer. In this randomized study, we found a frequent decrease of transferrin coinciding with the elevation of C3-proactivator and haptoglobin. The serum concentration of plasminogen and alpha 2-macroglobulin were rarely observed in the pathological range excluding cancer-associated changes. Tumor metabolites and/or the circulating immune complex may account for the alteration of transferrin, haptoglobin and C3-proactivator, more than primary cancer-related synthesis of these proteins.

Adenocarcinoma↗
PubMed2001

Rat uterine complement C3 expression as a model for progesterone receptor modulators: characterization of the new progestin trimegestone.

Progestins have a wide variety of activities in female reproduction. There are also pharmacological applications for progestins, including hormone replacement therapy and contraception. Here we report the development and characterization of the rat uterine complement component C3 mRNA as a molecular target for the evaluation of the antiestrogenic activity of progestins in the uterus. In this assay, ethinyl estradiol (EE) is used to stimulate C3 expression and progestins are then evaluated for their ability to inhibit this expression. The three reference progestins, progesterone (P4), levonorgestrel (LNG), and medroxyprogesterone acetate (MPA) blocked the increase in C3 mRNA levels induced by EE. Dexamethasone (DEX) and 17alpha-methyl testosterone did not inhibit the estrogen induced C3 mRNA levels; in fact, DEX caused a further increase in C3 mRNA levels. Finally, the antiprogestin RU486 was able to block the MPA inhibition of C3 message. RU486, like DEX, caused an increase in C3 mRNA levels above that of estrogen treatment alone. The model was also used to evaluate trimegestone (TMG), a new steroidal progestin, that has been shown to be a potent and selective progesterone receptor agonist. The activity of TMG in the rat uterine decidualization and ovulation inhibition assays was similar to MPA. However, in the C3 model, TMG caused a dose-dependent inhibition of the EE induced C3 message and was approximately five-fold more potent in this model than MPA (EC(50) of 4.7 microg/kg and 26.5 microg/kg, respectively). Therefore, TMG was a more potent antagonist of estrogenic activity in the uterine endometrium than any of the reference progestins tested and therefore may be more effective in protecting the endometrium in hormone replacement therapy.

Animals↗
PubMedDate not supplied

[Role of the complement C3 protein in the control of the specific immune response].

Whereas complement system was usually considered as a member of innate defence, one of its components (C3) is now thought to facilitate acquired immunity. This role is due first to its capacity to covalently bind to antigens and secondly to the interactions of its proteolytic fragments with different receptors expressed on most cells involved in the acquired immune response. After activation in the plasma, C3 is proteolysed in fragments which possess various biological activities, as a modification in cell activities occurred after binding to cell surface receptors. Injection of low amount of antigen results in a modified immune response in C3 deficient animals with a decrease in the level of specific antibodies and an absence of IgM/IgG switch. One of the fragments of C3 (C3d) and its receptor (CR2) seem particularly important : knock out animals in C3 or CR2 have similar phenotypes. Mice with a deficit in CR2 restricted to the B lymphocytes present a strong reduction in the number and the size of germinal centers. Moreover, expression of CR2 on follicular dendritic cells is necessary for the generation of a strong memory response. C3 is also involved in the control of the intracellular processing of the antigen as the use of covalent complex (C3b-antigen) instead of free antigen increases the amount of stable MHC class II molecules at the antigen presenting cells surface. In summary, C3 fragments increase cell to cell interactions, induce intracellular signalling after binding to their receptors and increases intracellular processing of antigens. A better knowledge of the different roles of C3 may be useful to modify the immune response and to promote the immune memory, a domain where C3 seems particularly important.

Animals↗
PubMed2003

Nonsense-codon-mediated decay in human hereditary complement C3 deficiency.

C3 occupies a central position in the complement pathway, mediating such diverse functions as convertase activity, opsonization and anaphylotoxin production. The deficiency of this protein is a rare autosomal recessive inherited disease, characterized by severe recurrent infections and immune complex disorders. We looked for molecular alterations that could explain the C3 deficiency present in a Brazilian boy of consanguineous parents who suffered from recurrent bacterial infections. Using reverse-transcriptase polymerase chain reaction to amplify C3 mRNA from LPS-stimulated fibroblasts from the patient, we demonstrated that his C3 gene has no large structural aberrations. However, after sequencing the amplified and cloned products we found: (1). a L314P amino acid substitution; (2). silent mutations at codons P577, S798 and A1437; and finally, (3). an R848STer substitution that results in the production of a truncated protein. Densitometry studies revealed a lower C3 mRNA concentration in the patient's fibroblasts, suggesting an inherent instability of his C3 mRNA. Our results indicate the presence of a premature termination codon in the C3 gene that results in a lack of the protein in patient's serum, which correlates with the acceleration of C3 mRNA decay in the patient's fibroblasts. This mRNA instability is consistent with a nonsense-codon-mediated decay process that ensures the elimination of possible deleterious truncated proteins, which, in the case of constitutively expressed abundant proteins such as C3, may otherwise accumulate to significant levels, leading to toxicity.

Amino Acid Substitution↗
PubMed2002

[Circulating immune complex and complement (C3) in a course of pulmonary tuberculosis].

The aim of the current study was to investigate plasma levels of Erythrocyte-Antibody (EA) and Erythrocyte-Antibody-Complement (EAC) circulating immune complexes (CIC) and C3 component of complement in 150 healthy volunteers and 29 patients with active tuberculosis before the treatment and 27 persons with inactive tuberculosis persons with pulmonary tuberculosis. The study showed the occurrence both of types CIC was higher in all groups of patients in comparison with the control (p < 0.001), while there was no significant differences in the patient's groups. The occurrence of CIC EA and EAC in tested groups was significantly greater than in the control (p < 0.001). The analysis of frequency of positive results obtained by RI EA test was showed an approximate percentage in the groups of patients both before antituberculous therapy and after two months treatment and was not significantly lower in inactive TB. The appearance of CIC EAC after two months treatment were significantly greater than in group with active TB (p < 0.01). In inactive TB, the higher occurrence of CIC were obtained by RI EAC test comparing with RI EA method (p < 0.01). On the contrary, in the patients with active TB the greater percentage was revealed using RI EA test (p < 0.05). In this group the examination of concentration of C3 was found higher mean (p < 0.05), whereas the values in patients with inactive TB were in the normal range. In patients after short therapy the level of C3 were decreased significant, when compared with control and other studied groups. The obtained results suggest that in all groups of patients occurrence inhibitor factor of rosettes EA and EAC; the CIC EA, EAC and C3 variability before and after short therapy can be results from the disease and/or application of medicines; the participation of CIC in the inactive stage of TB maybe suggest partially extinguished mycobacterial process.

Adolescent↗
PubMed2003

A corresponding tyrosine residue in the C2/factor B type A domain is a hot spot in the decay acceleration of the complement C3 convertases.

The cleavage of C3 by the C3 convertases (C3bBb and C4b2a) determines whether complement activation proceeds. Dissociation (decay acceleration) of these central enzymes by the regulators decay-accelerating factor (DAF), complement receptor 1 (CR1), factor H, and C4-binding protein (C4BP) controls their function. In a previous investigation, we obtained evidence implicating the alpha4/5 region of the type A domain of Bb (especially Tyr338) in decay acceleration of C3bBb and proposed this site as a potential interaction point with DAF and long homologous repeat A of CR1. Because portions of only two DAF complement control protein domains (CCPs), CCP2 and CCP3, are necessary to mediate its decay of the CP C3 convertase (as opposed to portions of at least three CCPs in all other cases, e.g. CCPs 1-3 of CR1), DAF/C4b2a provides the simplest structural model for this reaction. Therefore, we examined the importance of the C2 alpha4/5 site on decay acceleration of C4b2a. Functional C4b2a complexes made with the C2 Y327A mutant, the C2 homolog to factor B Y338A, were highly resistant to DAF, C4BP, and long homologous repeat A of CR1, whereas C2 substitutions in two nearby residues (N324A and L328A) resulted in partial resistance. Our new findings indicate that the alpha4/5 region of C2a is critical to decay acceleration mediated by DAF, C4BP, and CR1 and suggest that decay acceleration of C4b2a and C3bBb requires interaction of the convertase alpha4/5 region with a CCP2/CCP3 site of DAF or structurally homologous sites of CR1 and C4BP.

Amino Acid Sequence↗
PubMed1978

Complement C3 convertase: cell surface restriction of beta1H control and generation of restriction on neuraminidase-treated cells.

The alternative or properdin pathway of complement is primarily controlled by the endopeptidase C3b inactivator (C3bINA) and the nonproteolytic glycoprotein beta1H. The molecular mechanisms of control were investigated by performing binding studies of radiolabeled complement proteins to C3b bearing sheep erythrocytes (E(S)C3b). C3b was found to have distinct binding sites for beta1H, C3bINA, Factor B, and properdin. beta1H binding increased C3bINA binding 30-fold, while Factor B binding prevented C3bINA action on C3b and was competitive with beta1H binding. Properdin binding, which facilitates Factor B interaction with C3b, had no effect on the beta1H and C3bINA sites. Activators such as rabbit erythrocytes (E(R)) have previously been shown to interfere with the effectiveness of the control by C3bINA and beta1H, thereby allowing unrestricted formation of C3 convertase. Such restriction of control does not occur on the surface of E(S), a nonactivator of the alternative pathway. On the basis of comparative binding studies, restriction of control is explained entirely by reduced binding of beta1H to E(R)C3b relative to E(S)C3b. Access of properdin, Factor B, C3bINA, and the Fab fragment of anti-C3 to the two cell types was unrestricted. Restriction of beta1H control could be generated on the surface of E(S) by removal of cell-surface sialic acid with neuraminidase (acylneuraminyl hydrolase; EC 3.2.1.18). This enzymatic treatment converted E(S) from a nonactivator to an activator of the alternative pathway.

Binding Sites↗
PubMed1989

Estrogen regulation of tissue-specific expression of complement C3.

The administration of estradiol to immature rats results in the increased synthesis and secretion of a 180-kDa protein, composed of 115- and 65-kDa subunits, by the uterine luminal epithelial cells. A monoclonal antibody against the 180-kDa protein was utilized to isolate the corresponding cDNA (LE-1) from a rat uterine luminal epithelial cell cDNA lambda gt11 expression library. This LE-1 cDNA was sequenced and shown to be homologous to complement component C3. The sequence was approximately 81 and 90% homologous to human and mouse C3, respectively. The LE-1 cDNA sequence was homologous with the 3' portion of the C3 mRNA containing the alpha subunit (115 kDa). Uterine mRNA isolated from immature rats treated with 1 microgram of estradiol for 24 h demonstrated a 25-fold increase in the concentration of a 6.0-kilobase mRNA by Northern hybridization with either LE-1 or authentic human C3 cDNA probes. To further examine the possibility that the estradiol-regulated secretory protein was C3, an aliquot of radiolabeled media protein from control and estradiol-stimulated rat uteri was incubated with goat anti-rat C3 antibody. The immunoprecipitated radiolabeled protein from estradiol-treated animals was increased significantly (p less than 0.01) compared to media from control animals. Analysis of the immunoprecipitated proteins on nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a single protein of 180 kDa from estradiol-stimulated uterine media, whereas no detectable proteins were immunoprecipitated from media obtained from control uteri. Also, when the immunoprecipitated protein was reduced (20 mM dithiothreitol) it dissociated into two subunits of 115 and 65 kDa. Immunohistochemical studies demonstrated the presence of C3 only in the epithelial cells of estrogen-stimulated rat uteri. In addition, the estradiol-stimulated mRNA was only detectable in uterine epithelial cell RNA. Analysis of liver RNA demonstrated a 6.0-kilobase mRNA, as in the uterus, when hybridized with LE-1. However, unlike the uterus, its concentration was not influenced by estrogen administration with up to three daily injections of 100 micrograms of diethylstilbestrol. Based on biophysical, DNA sequence, and antibody data we conclude that rat uterine epithelial cells produce C3 in response to estradiol whereas the expression in the liver was not modulated by estrogens.

Animals↗
PubMed2004

Influence of complement C3 amount on IgG responses in early life: immunization with C3b-conjugated antigen increases murine neonatal antibody responses.

Complement component C3, which plays an important role in both the innate and adaptative immune response, is present at low level in human infants. We show here that: (i) serum C3 amount is weak also in infant mice, (ii) these young animals fail to upregulate C3 to adult levels following tetanus toxoid immunization, (iii) neonatal macrophages have a limited capacity to synthesize C3 upon LPS exposure, (iv) conjugation of antigen to C3b significantly enhances antibody response elicited in 1-week-old mice--although it does not increase primary IgG response in adult mice. Altogether, this identifies C3 as one of the factors limiting early life antibody response and emphasizes the potential interest of immunization strategies overcoming this limitation.

Age Factors↗
PubMed1993

Identification of a major binding site for complement C3 on the IgG1 heavy chain.

Activation of the alternative pathway of complement by immune complexes involves the covalent attachment of the third component (C3) to the IgG heavy chain. In order to localize the site/sites of attachment, adducts of human C3.IgG were digested in situ with endoproteinase Lys-C and Staphylococcus aureus V8 protease, and the fragments were analyzed. The dimeric peptide containing the covalent bond, identified by alkylation of the free thiol group (Cys1010) with iodo[14C]acetamide, was isolated by high-performance liquid chromatography fractionation. A double sequence with NH2 termini corresponding to position 134 of IgG heavy chain and position 1002 of the C3 alpha' chain was found by analysis with automated Edman degradation. The intact dimeric peptide had a mass of 3453 Da and was composed of IgG and C3 fragments with predicted sizes of 23 and 12 residues, respectively. The IgG peptide includes a cluster of six potential acceptor sites for ester bond formation. Thus, it appears that C3 binding is limited to a single region within the CH1 domain of the IgG1 heavy chain.

Amino Acid Sequence↗