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PubMed1993

Endogenous complement C3 synthesis in immune complex nephritis.

Human renal epithelial and mesangial cells have been shown to synthesise complement C3 in culture, but the relevance of this finding to the development of complement-mediated nephritis is uncertain. We investigated C3 gene expression in tissue biopsies that showed three main categories of renal injury. By semiquantitative polymerase chain reaction, biopsies from patients with immune-complex glomerulonephritis and those with cell-mediated interstitial nephritis showed increased C3 expression (p < 0.05), but biopsies from patients with non-immune glomerular injury did not. These findings suggest that local C3 production is enhanced in immune-mediated nephritis and are consistent with the hypothesis that locally synthesised complement components are involved in the pathogenesis of tissue injury.

Complement C3c↗
PubMed2000

Transforming growth factor-beta1 acts as a potent inhibitor of complement C3 biosynthesis in human pancreatic cancer cell lines.

In this study, we attempted to determine how transforming growth factor (TGF)-beta1 affects complement C3 secretion in the pancreatic cancer cell lines PANC-1 and BxPC-3. We also compared the responses in C3 secretion with those in interleukin (IL)-8 secretion. The C3 and IL-8 expression was evaluated at the protein and messenger RNA (mRNA) levels. The activation of nuclear factor-kappaB (NF-kappaB) was assessed by an electrophoretic gel mobility shift assay (EMSA). IL-1beta and tumor necrosis factor (TNF)-alpha both induced a marked increase in C3 and IL-8 secretion. However, TGF-beta1 potently decreased the IL-1beta- and TNF-alpha-induced C3 secretion, whereas the IL-8 secretion was weakly but significantly enhanced. These responses were also observed at the mRNA level. In PANC-1 cells, IL-1beta and TNF-alpha induced a rapid activation of nuclear factor (NF)-kappaB, and TGF-beta1 enhanced this activation slightly. The induction of Fos protein has been reported to be required for the inhibitory action of TGF-beta1, and the translocation of Fos protein into the nucleus was associated with TGF-beta1 stimulation in PANC-1 cells. Our results suggest that TGF-beta1 may act as a potent inhibitor of C3 secretion in pancreatic cancer cell lines under inflammatory conditions. This action of TGF-beta1 did not correlate with NF-kappaB activation, but associated with the translocation of Fos protein into the nucleus.

Antibodies↗
PubMed1995

Production of the third component of complement (C3) by peripheral polymorphonuclear neutrophils of the patients with rheumatoid arthritis.

Normal human polymorphonuclear neutrophils (PMN) can spontaneously produce the third component of complement (C3) in in vitro culture as detected by ELISA. This C3-producing capacity of PMN can be augmented by TNF-alpha (20 ng/ml) and bacterial lipopolysaccharide (100 ng/ml), but not by IL-1 beta or IL-8. The C3 production by PMN was found to be temperature dependent and was suppressed by the addition of protein inhibitor. The C3 mRNA in PMN could be detected by reverse transcription assisted polymerase chain reaction (RT-PCR) after TNF-alpha or LPS stimulation for 6 hours. To further understand C3 production by peripheral blood PMN in rheumatoid arthritis (RA), spontaneous and TNF-alpha stimulated production of C3 by peripheral PMN were compared in 15 cases of active RA, 15 inactive RA and 15 normal individuals. We failed to find any significant difference among the three groups. We conclude that PMN plays a negligible role in C3 hypercomplementemia in patients with active RA.

Arthritis, Rheumatoid↗
PubMed1984

Linkage of the LW blood group locus with the complement C3 and Lutheran blood group loci.

Segregation data on LW in families of informative males show that the LW (Landsteiner-Wiener) blood group locus is closely linked to the complement C3 locus and to the locus for the Lutheran blood group. This finding also confirms the presence of a larger linkage group on chromosome 19, including now the loci for apoE, Le, C3, LW, Lu, Se, H, PEPD, myotonic dystrophy (DM), neurofibromatosis (NF) and familial hypercholesterolemia (FHC). Linkage of LW with the Lewis blood group locus could not be definitely established by the present family data, but small positive scores between LW and Le suggest that the Le locus is situated outside the C3-LW region.

Chromosomes, Human, 19-20↗
PubMed1993

The secretion of the third component of complement (C3) by human polymorphonuclear leucocytes from both normal and systemic lupus erythematosus cases.

Recently, murine peritoneal exudate polymorphonuclear leucocytes (PMNs) have been proved to secrete complement C3. In this report we show the secretion of C3 by normal human blood PMNs. ELISA assay was used to detect secreted C3 in culture supernatants of PMNs, while immunoperoxidase staining was used for intracellular C3 detection. 12-o-tetradecanoyl phorbol 13 acetate (TPA) had a flushing effect on C3 secretion by PMNs but not macrophages, suggesting a special C3 storing capability in PMNs. Dioctanoyl glycerol, mezerein and calcium ionophore A23187 caused the same marked increase in C3 secretion by PMNs. This suggests the contribution of protein kinase C and the calmodulin pathway in the mechanism of C3 secretion, similar to murine peritoneal exudate PMNs. In some cases of systemic lupus erythematosus, C3 secretion by blood PMNs was increased but no similar response to TPA could be detected.

Cells, Cultured↗
PubMed1992

1 alpha,25-dihydroxyvitamin D3 regulates in vivo production of the third component of complement (C3) in bone.

We previously reported that 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2D3] specifically stimulates production of the third component of complement (C3) by murine osteoblastic cells and marrow-derived stromal cells (ST2) in vitro. In the present study we examined tissue-specific production of C3 in vivo in vitamin D-deficient mice, some of which received supplemental 1 alpha,25-(OH)2D3. Western blot analysis indicated that the C3 protein band in bone was undetectable in vitamin D-deficient mice, but became distinct 48 h after 1 alpha,25-(OH)2D3 administration. The mRNA expression of C3 in bone was also undetectable in vitamin D-deficient mice and appeared as early as 24 h after 1 alpha,25-(OH)2D3 administration. mRNA expression apparently preceded the appearance of C3 protein. In contrast, there was no significant difference in the expression of hepatic C3 mRNA among normal mice fed laboratory chow and vitamin D-deficient mice with and without 1 alpha,25-(OH)2D3 administration. The serum concentration of C3 in vitamin D-deficient mice was almost identical to that in normal mice and was unchanged after 1 alpha,25-(OH)2D3 administration. 1 alpha,25-(OH)2D3 receptor (VDR) mRNAs were detected in the kidney and intestine, whereas no appreciable mRNA expression of VDR occurred in the liver. Osteopontin mRNA was expressed in response to 1 alpha,25-(OH)2D3 in the kidney, but not in the intestine. Immunohistochemical studies showed that in normal mice, the C3 protein was located mainly in the periosteal regions of calvaria and on the surfaces of bone trabeculae in the tibial metaphyses. These results demonstrate that 1 alpha,25-(OH)2D3 tissue-specifically regulates in vivo production of C3 in bone. The production of bone C3 cannot be attributed to the presence of VDR alone, and we speculate that other tissue-specific factors are required.

Animals↗
PubMed1992

Fc gamma R-dependent regulation of the biosynthesis of complement C3 by murine macrophages: the modulatory effect of IL-6.

The effect of murine IgG isotypes on the gene expression and secretion of the third component of complement (C3) has been studied using the monocytoid cell line P388D1 and oil-elicited mouse peritoneal macrophages. It is demonstrated that the binding of IgG2a and IgG2b but not IgG1 and IgG3 augments the biosynthesis of C3 both in the presence and in the absence of the phorbol ester, phorbol myristate acetate in the case of both cell types. The multifunctional cytokine interleukin-6 (IL-6) alone reveals no effect on the gene expression of C3, but increases the effectiveness of mouse IgG2a and IgG2b. Confirming the role of Fc gamma RII, a strong up-regulation of C3 gene expression and C3 secretion was found when macrophages were cultured with the F(ab')2 fragment of the Fc gamma RII-specific monoclonal antibody 2.4G2.

Animals↗
PubMed1992

Primary structure of cobra complement component C3.

Complement component C3 is a multifunctional protein known to interact specifically with more than 10 different plasma proteins or cell surface receptors. Cobra venom contains cobra venom factor, a structural analogue of C3 that shares some properties with C3 (e.g., formation of a C3/C5 convertase) but differs in others (e.g., susceptibility to regulation by factors H and I). The elucidation of structural differences between C3 and cobra venom factor can be expected to help identify functionally important regions of C3 molecules. To that end we have undertaken the molecular cloning of both cobra C3 and cobra venom factor to take advantage of the unique biologic system where both proteins are produced by the same species. We report the primary structure of cobra C3 mRNA and the derived protein structure. Cobra C3 mRNA is 5211 bp in length. It contains an open reading frame of 4953 bp coding for a single pre-pro-C3 molecule, consisting of a 22-amino acid signal sequence, a 633-amino acid beta-chain (70 kDa), and a 992-amino acid alpha-chain (112 kDa) which is separated from the beta-chain by four arginine residues. There are no N-glycosylation sites in cobra C3. Cobra C3 exhibits approximately 58% nucleotide sequence identity with C3 from mammalian species. At the protein level, sequence identity is approximately 52% and sequence similarity approximately 71%. All 27 cysteine residues are highly conserved as are the C3 convertase cleavage site, the thioester site, and the factor B binding site. Cobra C3 also seems to have homologous binding sites for factor H and properdin, as well as a conserved sequence in the functionally important region of the C3a anaphylatoxin. The sequence homology at the CR2 and CR3 binding sites does not exceed the overall sequence homology. Accordingly, the existence of CR2 and CR3 binding sites can neither be deduced nor excluded.

Amino Acid Sequence↗
PubMed1998

Endotoxemia in mice stimulates production of complement C3 and serum amyloid A in mucosa of small intestine.

We examined the effect of endotoxemia in mice on protein and mRNA levels for the acute phase proteins complement C3 and serum amyloid A (SAA) in jejunal mucosa. Endotoxemia was induced in mice by the subcutaneous injection of 250 microg lipopolysaccharide per mouse. Control mice were injected with saline. C3 and SAA were measured by ELISA. Messenger RNA levels were determined by Northern blot analysis or competitive PCR. Immunohistochemistry was performed to determine in which cell type(s) C3 and SAA were present. Mucosal C3 and SAA protein and mRNA levels were increased in endotoxemic mice. Immunohistochemistry showed that C3 was present in both enterocytes and cells of the lamina propria, whereas SAA was seen mainly in lamina propria cells. Results suggest that endotoxemia stimulates production of C3 and SAA in small intestinal mucosa. The response may be regulated at the transcriptional level and probably reflects increased synthesis of the acute phase proteins in both enterocytes and cells of the lamina propria.

Animals↗
PubMed1975

Deposits of immunoglobulins and complement C3 in clinically normal skin of patients with lupus erythematosus.

Deposits of immunoglobulins and/or complement C3 were found in two-thirds of biopsies from clinically normal skin of 64 patients with systemic lupus erythematosus, as judged by well defined criteria. The incidence of deposits in clinically normal skin was identical in patients with and without clinical skin lesions. IgM was found more frequently in the deposits (88%) than was IgG (36%) but equally frequently in involved and uninvolved skin, whereas C3 was found more often in patients with skin lesions (59% in involved skin, 36% in uninvolved skin) than in patients without skin lesions (14%). The occurrence of IgG and IgA was less frequent than that of C3 but the distribution was similar to that of C3. In normal skin of 20 patients with chronic discoid LE, deposits were found in one. Deposits were found in the skin of one-third of patients with nuclear antibodies in their sera and symptoms compatible with SLE but with a score of symptoms too low to meet the criteria.

Adolescent↗
PubMed1993

Differential expression of complement C3 and C4 in the human kidney.

Complement activation is associated with a variety of immunologically-mediated renal diseases. Proximal tubular epithelial cells in situ constitutively express messenger RNA for C4 of the complement system. These same epithelial cells in culture have been reported to contain message for C3 and to secrete this protein when stimulated by IL-2. The present study compared the in situ localization of C3 and C4 message in parallel in a variety of renal biopsy and nephrectomy specimens. All adequate tissue samples (n = 23) had C4 mRNA throughout in the cortical tubular epithelium. Although C3 message was also expressed in tubular epithelial cells, there was much greater variation in its distribution. mRNA for C3 was not detected in histologically normal specimens (n = 4) either by in situ or Northern hybridization. Focal C3 message correlated with focal histologic abnormalities (e.g., focal glomerulosclerosis), while more generalized C3 signal occurred in specimens with more diffuse inflammatory processes (e.g., SLE). Infiltrating inflammatory cells and cells of the glomeruli were uniformly negative for C3 (and C4) message. Tubular C3 and C4 mRNA appeared to be translated, since selected specimens showed cytoplasmic staining by monoclonal antibodies to C3c and C4c. These observations are consistent with the hypothesis that local production of inflammatory mediators could induce C3 synthesis in the renal interstitium, with the possibility that subsequent complement activation could enhance the pathogenic process.

Complement C3↗
PubMed1997

Diversity of the third form of complement, C3, in fish: functional characterization of five forms of C3 in the diploid fish Sparus aurata.

We have recently shown that Sparus aurata, the gilthead sea bream (a diploid species), similarly to rainbow trout (a quasi-tetraploid species), possesses multiple forms of the third form of complement (C3). In the present study we have evaluated the ability of the gilthead sea bream proteins to function as active C3 molecules. All five C3 isoforms could be fixed covalently to sheep erythrocyte ghosts and were able to bind to various complement-activating surfaces in the presence of MgEGTA. In the absence of MgEGTA their binding capacities generally increased, presumably as a result of classical-pathway activation by the natural antibodies present in the serum. The presence of EDTA abrogated the binding of all C3 isoforms to the various surfaces tested. The C3 isoforms differed in the efficiency of their binding to complement-activating surfaces: the two most abundant C3 isoforms (C3-1 and C3-2) bound to zymosan as well as to sheep and rabbit erythrocyte ghosts, whereas C3-3, C3-4 and C3-5 were unable to bind to zymosan. Upon complement activation, all five C3 isoforms were cleaved to 'iC3b' by factor H and I-like proteins, generating fragments similar to those generated from C3 molecules of other species. Furthermore the degradation of methylamine-hydrolysed C3 isoforms to iC3b was significantly inhibited by EDTA. The structural and functional diversity that we have observed in the C3 isoforms of S. aurata would increase the capacity of this fish to recognize a broader spectrum of potential pathogens and reinforce a specific immune response, which in fish is delayed compared with that of higher vertebrates, and is based on a single Ig type (IgM).

Animals↗
PubMed1986

Biosynthesis of the third component of complement (C3) by the human monocytic-cell line U-937. Induction by phorbol myristate acetate.

Phorbol myristate acetate (PMA)-stimulated human monocyte-like cells (U-937) were found to synthesize the third component of complement (C3), as shown by enzyme-linked immunosorbent assay and immunoprecipitation from [35S]methionine-labelled culture supernatants. C3 synthesis occurred at a rate of about 160 ng of C3/24 h per 10(6) cells on day 7 after addition of PMA; it was blocked by cycloheximide treatment and was restored after removal of the inhibitor. SDS/polyacrylamide-gel-electrophoretic analysis of the immunoprecipitated protein showed that the size and subunit structure of the newly synthesized C3 were identical with those of plasma C3, and that a single-chain intracellular precursor was present in the cell lysates. Haemolytic assays showed that the synthesized C3 fully expressed functional activity in early culture within 4 h. After longer culture, a loss of haemolytic activity was observed. The possibility that newly secreted C3 is cleaved by U-937 cells themselves was suggested.

Cell Line↗
PubMed1983

Location of immunoglobulins and complement (C3) at the surface and within the skin of dogs.

The serum proteins present at the skin surface in dogs were found to include the immunoglobulins (Ig) G, M and A, complement (C3) and albumin. Within the skin IgG and IgM were consistently found in the interstitial tissue throughout the dermis and were commonly present in the dermal blood vessels and hair papillae. IgA was undetectable or present in small amounts in the dermis in most of the 16 samples examined. It was found in the sweat glands, both in the lumen and the fundic epithelium, in some skin samples. C3 was demonstrated in the dermis and in the inter-cellular spaces of the stratum corneum. Elution of fresh skin specimens with phosphate buffered saline removed the majority of interstitial immunoglobulin and C3 from the dermis and some of the IgA from the sweat glands. IgM could still be demonstrated in the region of the epidermal basement membrane and C3 was not eluted from the stratum corneum. Removal of interstitial IgG and IgM facilitated the identification of immunoglobulin-bearing cells in the dermis. The distribution of IgG and IgM in dog skin is similar to that found in ruminants. Demonstration of IgA in the canine sweat gland fundus lends further support to the concept of IgA as a secretory immunoglobulin in the skin.

Albumins↗
PubMed1990

Complement C3 deposition onto bacteria by neonatal serum is not enhanced after the infusion of intravenous immunoglobulin.

To determine the effect of intravenous immunoglobulin (IVIG) on the capacity of serum from septic neonates to deposit complement C3 and IgG onto the bacteria isolated from their blood, 500 mg/kg of IVIG was administered to 18 neonates suspected of being septic. Blood was obtained just before the infusion, and again 15 minutes after its completion. Group B streptococcus type II, group B streptococcus type III, Staphylococcus aureus, and Staphylococcus epidermidis were isolated from the pre-infusion blood of four neonates. Bacteria were incubated with the appropriate serum, washed, and the amount of C3 and IgG subsequently bound to the organisms was quantified by radioimmunobinding assay. Sera from the four septic neonates and sera from four neonates of similar gestational age but whose blood cultures were negative were compared with pooled sera from healthy adults. Before the administration of IVIG, C3 deposition onto the bacteria by sera from five of the seven neonates tested was significantly less than that observed for adult sera. Following the infusion, no increase in C3 deposition was observed for any of the seven sera assayed, and in two cases C3 deposition fell significantly. In contrast, in seven of eight cases, IVIG enhanced the IgG deposition to levels greater than or equal to those observed for adult sera. Therefore, following the infusion of IVIG into neonates with proven or suspected sepsis, the deposition of C3 onto invasive bacteria by their serum was not enhanced even though IgG deposition was increased.

Antibodies, Viral↗
PubMed1992

PEO enhancement of platelet deposition, fibrinogen deposition, and complement C3 activation.

Whereas it has been commonly thought that adding polyethylene oxide PEO to a surface would diminish the capacity of the surface to cause deposition of platelets and of fibrinogen, and to activate complement C3, we present data showing exactly the opposite. These unexpected results are obtained with low molecular weight (2000) PEO, and are not found with higher molecular weight (20,000) PEO.

Animals↗
PubMed1988

Analysis of the interactions between properdin, the third component of complement (C3), and its physiological activation products.

The interactions of properdin with both surface-bound and fluid-phase C3 (the third component of complement) and its activation products have been investigated by using a purified preparation of the 'native' form. At physiological ionic strength, a weak interaction with cell-bound C3b (the larger activation fragment of C3) could be demonstrated. In the presence of Factor B this interaction was enhanced, and further enhancement was seen when C3bBb sites were formed on the erythrocytes. The avidities of properdin for cell-bound iC3b (the initial product of Factors I and H action on C3b) and C3b were compared at low ionic strength, with that measured for iC3b being less than that for C3b. In contrast, the affinities of properdin for fluid-phase C3b, iC3b and C3c (the larger product of Factors I and H or CR1 (the C3b receptor) action on iC3b) were all very similar, and apparently much weaker than that for cell-bound C3b. No interaction with either native C3 or, more surprisingly, C3i (haemolytically inactive C3) could be detected. Properdin also inhibited Factor I binding to, and action upon, cell-bound C3b, but did not inhibit Factor I action on fluid-phase C3b. These data permit a more detailed description of the roles of properdin in the alternative pathway of complement activation, emphasizing its importance in concentrating activation at the activating surface.

Complement Activation↗