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PubMed1998

Detection of complement C3 and factor B gene expression in normal colorectal mucosa, adenomas and carcinomas.

Local secretion of complement components in the human intestine has been previously reported. However, the cellular source has not been identified. In this study, we demonstrate complement C3 and factor B mRNA expression in the normal colonic mucosa by in situ hybridization analysis. C3 and factor B genes were found to be expressed at high levels in the epithelial cells of the lower parts of the crypts in colonic mucosa, and this expression decreased gradually from the crypt base to the luminal surface. At the upper crypt and the luminal surface, these genes almost disappeared. C3 and factor B genes were expressed in all crypts at the same level. Furthermore, C3 and factor B gene expression was also identified in adenomas and carcinomas. In these neoplastic tissues, C3 and factor B genes were expressed uniformly, and the polarized distribution observed in the normal crypts was not detected. It is likely that complement components are locally synthesized in the intestine, and that these complement components may actively participate in normal immune and inflammatory responses over the enormous surface area of the intestinal mucosa.

Adenoma↗
PubMed1985

Relationship between the third component of human complement (C3) bound to stored preserved erythrocytes and their viability in vivo.

In this study we evaluated whether the 4 degrees C storage-induced coating of red blood cells (RBC) with molecules of the third component of human complement, C3, affects the viability of the preserved RBC. To this end, we determined whether the amount of C3 bound to preserved RBC correlated with the 24-hour survival value. The % anti-C3c-induced agglutination of stored RBC provided an estimate of the amount of RBC-bound C3. In some cases, the number of RBC-bound C3c-containing molecules was also quantitated. The 24-hour survival of autologous RBC was measured in 114 cases. All units were initially stored at 4 degrees C as RBC concentrates followed in 21 cases by frozen storage and in 75 cases by biochemical rejuvenation and frozen storage. The data showed a significant correlation between % anti-C3c-induced agglutination of the preserved RBC and the length of 4 degrees C storage of the RBC concentrates. Neither freezing nor rejuvenation cleaved the C3c fragment from stored RBC. The 24-hour survival was significantly and negatively correlated with both the storage length of RBC concentrates at 4 degrees C and with the amount of RBC-bound C3 but not with RBC ATP level. These data suggest that the RBC-bound C3 either contributes to or is a marker for the extent of the preservation injury of RBC.

Adenosine Triphosphate↗
PubMed2001

Complement and myoblast transfer therapy: donor myoblast survival is enhanced following depletion of host complement C3 using cobra venom factor, but not in the absence of C5.

Myoblast transfer therapy (MTT) is a potential cell therapy for myopathies such as Duchenne Muscular Dystrophy and involves the injection of cultured muscle precursor cells ('myoblasts') isolated from normal donor skeletal muscles into dystrophic host muscle. The failure of donor myoblast survival following MTT is widely accepted as being due to the immune response of the host. The role of complement as one possible mechanism for the initial, very rapid death of myoblasts following MTT was investigated. Donor male myoblasts were injected into the tibialis anterior (TA) muscles of female host mice that were: (i) untreated; (ii) depleted of C3 complement (24 h prior to MTT) using cobra venom factor (CVF); and/or (iii) deficient in C5 complement. Quantification of surviving male donor myoblast DNA was performed using the Y-chromosome specific (Y1) probe on slot blots for samples taken at 0 h, 1 h, 24 h, 1 week and 3 weeks after MTT. Peripheral depletion of C3 was confirmed using double immunodiffusion, and local depletion of C3 in host TA muscles was confirmed by immunostaining of muscle samples. Cobra venom factor treatment significantly increased the initial survival of donor myoblasts, but there was a marked decline in myoblast numbers after 1 h and little long-term benefit by 3 weeks. Strain specific variation in the immediate survival of donor male myoblasts following MTT in untreated C57BL/10Sn, DBA-1 and DBA-2 (C5-deficient) female hosts was observed. Cobra venom factor depletion of C3 increased initial donor male myoblast survival (approximately twofold at 0 h) in C57BL/10Sn and DBA-1 host mice and approximately threefold in DBA-2 hosts at 0 h and 1 h after MTT. The rapid and extensive number (approximately 90%) of donor male myoblasts in untreated DBA-2 mice (that lack C5) indicates that activation of the membrane attack complex (MAC) plays no role in this massive initial cell death. The observation that myoblast survival was increased in all mice treated with CVF suggests that CVF may indirectly enhance donor myoblast survival by a mechanism possibly involving activated C3 fragments.

Animals↗
PubMed2001

Degradation of bovine complement C3 by trichomonad extracellular proteinase.

Bovine trichomoniasis is a local infection of the reproductive tract making interaction with mucosal host defenses crucial. Since the parasite is susceptible to killing by bovine complement, we investigated the role of the third component of complement (C3) in host parasite interactions. Bovine C3 was purified by anionic and cationic exchange chromatography. The purified protein was characterized by immunoreactivity, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and peptide sequencing of the amino terminus of the beta chain. When purified bovine C3 was incubated for varying time periods with trichomonad extracellular proteinases, SDS-PAGE gels revealed digestion of the alpha chain to small fragments. Such degradation in vivo would prevent formation of C3b and completion of the complement cascade, resulting in evasion of killing. To evaluate the relevance of this data, we determined whether C3 was present in bovine genital secretions. With a quantitative ELISA assay, C3 could be demonstrated in both uterine and vaginal washes. To our knowledge, this is the first demonstration of bovine C3 in genital secretions. The C3 concentration increased significantly in vaginal secretions by 8 and 10 weeks in heifers infected with Tritrichomonas foetus. An increase was also seen in uterine secretions of infected heifers, but sample numbers were insufficient for statistical analysis. Transcription of the major extracellular cysteine proteinase (TFCP8) was demonstrated in T. foetus cells from uterine secretions of infected heifers by RT-PCR and Southern blotting. The results indicate that C3 may be important in genital defense and that trichomonad extracellular proteinases may play a role in evasion of complement-mediated killing.

Animals↗
PubMed2003

Tolerance is dependent on complement C3 fragment iC3b binding to antigen-presenting cells.

Systemic tolerance can be induced by the introduction of antigen into an immune-privileged site. Here we investigated the role of complement in the induction of tolerance after intraocular injection. We found that the development of antigen-specific tolerance is dependent on a complement activation product. The ligation of the complement C3 activation product iC3b to complement receptor type 3 (the iC3b receptor) on antigen-presenting cells resulted in the sequential production of transforming growth factor-beta2 and interleukin-10, which is essential for the induction of tolerance. These observations may extend to the development of both neonatal tolerance and other forms of acquired tolerance.

Animals↗
PubMed1977

Deposits of immunoglobulin G and complement C3 in recurrent aphthous ulcerations.

Deposits of immunoglobulin G (IgG) were demonstrated at the basement membrane zone in lesions from 14 out of 16 patients with recurrent aphthous ulcerations (RAU) by means of an immunofluorescent (IF) staining technique. Deposits of complement C3 were demonstrated at the same localization in lesions from 16 out of 16 patients with RAU. Similar deposits of C3 were demonstrated in 11 out of 12 experimentally produced oral wounds (EOW). Immunoglobulin deposits were not detected in the EOW. No deposits of immunoglobulin or C3 were revealed in 12 biopsies from normal oral mucosa (NOM). Further, the IF investigation demonstrated circulating autoantibodies against the cytoplasm of autologous oral epithelial cells in patients with RAU. The specificity of the present immunologic reactions and their possible role in the pathogenesis of RAU are discussed.

Adult↗
PubMed1990

Correlation between circulating schistosomal antigen, schistosomal complement C3 and intensity of infection.

53.7% of the already parasitologically proved schistosomiasis cases showed circulating schistosomal antigen (C.S.A.) in their sera with significantly higher levels than the controls, with no correlation between the level of C.S.A. and the foecal egg count. Significant higher levels of schistosomal complement C3 were found in schistosomiasis patients as compared to the control group, with no significant difference in the mean level of C3 between patients with positive and negative C.S.A.

Adolescent↗
PubMed2001

Transferrin but not albumin mediates stimulation of complement C3 biosynthesis in human proximal tubular epithelial cells.

Complement is increasingly implicated in the pathogenesis of progressive renal disease resulting from persistent proteinuria. We have previously shown that apical serum proteins stimulate C3 in cultured human proximal tubular epithelial cells (PTECs), and that the stimulant is a nonalbumin compound of 30 to 100 kd. We postulated in this study that transferrin and apotransferrin, also important components of proteinuric urine in this molecular-weight range, might be the culprit. Human PTECs were obtained by differential sieving of renal cortical tissue from the normal pole of tumor nephrectomy specimens and characterized to be predominantly of proximal tubular origin. Complement C3 messenger RNA (mRNA) expression was analyzed in confluent growth-arrested PTEC monolayers in media containing different concentrations (2.5 to 20 mg/mL) of transferrin by reverse transcription and polymerase chain reaction. Pure human albumin was used as a control protein. C3 protein secretion was detected and quantified by a sandwich enzyme-linked immunosorbent assay on cell culture supernatants after distinct time points. Transferrin enhanced the rate of C3 secretion in a dose-dependent manner, reaching maximal stimulation at doses of 10 mg/mL. Selected experiments using the Transwell technique showed that C3 release was predominantly apical in the resting state. The addition of 10 mg/mL of transferrin apically but not basolaterally stimulated both apical and basolateral C3 secretion and increased the basolateral-apical ratio of C3 secretion from 0.45 +/- 0.16 to 0.93 +/- 0.24 (P: < 0.02). Constitutive C3 mRNA expression was upregulated by transferrin in a time- and dose-dependent fashion, reaching a peak after 24 hours. A similar degree of C3 upregulation was reproduced when iron-poor transferrin, apotransferrin, was used instead. These results indicate that C3 synthesis in PTECs is upregulated by transferrin, for which protein rather than iron moiety may account for the observed effects. These findings provide evidence linking proteinuria with overexpression of tubular complement.

Apoproteins↗
PubMed1991

Complement C3 synthesis, peroxidase activity and eosinophil chemotaxis in the rat uterus: effect of estradiol and testosterone.

Treatment of immature rats with estradiol (E2) produced a large increase in uterine peroxidase activity which was accompanied by an increase in eosinophil chemotactic factor (ECF-U). The synthesis of complement C3 was also induced in the uterus and the amount of this 180 kDa protein was determined both by immunoprecipitation and after separation by polyacrylamide gel electrophoresis. Testosterone (T) did not produce an increase in any of these parameters although it antagonized the estrogen-induced increase in uterine peroxidase activity and these effects were more pronounced in estrogen-primed animals. This antagonism was prevented by the antiandrogen, flutamide. Testosterone showed little effect on eosinophil chemotactic activity and did not inhibit the E2-stimulated synthesis of C3. The results with T were supported by the lack of any significant effect by flutamide which antagonizes receptor-mediated androgenic events. These findings are discussed in relation to the action of other types of hormonal steroids (progesterone, dexamethasone) in inhibiting these estrogen-induced molecular changes in the rat uterus and contribute to our understanding of steroid-steroid interaction and the regulation of uterine function.

Animals↗
PubMed1991

Transcriptional regulation of the production of the third component of complement (C3) by 1 alpha,25-dihydroxyvitamin D3 in mouse marrow-derived stromal cells (ST2) and primary osteoblastic cells.

We have purified a 190-kDa protein produced by mouse marrow-derived stromal cells (ST2) in response to 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2D3] and unequivocally identified it as mouse complement C3 (C3). In this study we examined the regulation by 1 alpha,25-(OH)2D3 of C3 production in ST2 cells at both the transcriptional and translational levels. 1 alpha,25-(OH)2D3 greatly increased the protein production of C3 at 24 h, and it attained a maximum at 72 h. C3 mRNA stimulation by 1 alpha,25-(OH)2D3 was initiated at 12 h and reached a maximum at 48 h. 1 alpha,25-(OH)2D3 increased the expression of C3 mRNA dose-dependently, ranging from 10(-10)-10(-8) M. The increase in the C3 production in response to 1 alpha,25-(OH)2D3 appeared to occur at a transcriptional level, since actinomycin-D completely inhibited both mRNA expression and protein production of C3 induced by 1 alpha,25-(OH)2D3. Besides 1 alpha,25-(OH)2D3, local bone-resorbing agents, such as interleukin-1 alpha, tumor necrosis factor-alpha, and lipopolysaccharides, also stimulated the expression of C3 mRNA, not only in ST2 cells, but also in primary osteoblastic cells. C3 production by hepatocytes occurred regardless of the presence or absence of 1 alpha,25-(OH)2D3. These results clearly indicate that 1 alpha,25-(OH)2D3 tissue-specifically regulates the synthesis of C3 in bone. Bone C3 may play an important role in bone metabolism.

Animals↗
PubMed2001

Cutting edge: myeloid complement C3 enhances the humoral response to peripheral viral infection.

HSV-1 is the causative agent of cutaneous lesions, commonly referred to as cold sores. Primary exposure to the virus ordinarily occurs through the periphery, in particular through abraded skin or mucosal membranes. Under certain circumstances (e.g., in neonatals or AIDS patients), the infection becomes disseminated, often with severe consequences. Spread of HSV-1 is limited by virus-specific Ab. The development of an efficient humoral response to the virus is dependent on innate immunity component complement C3. The liver is the major source of C3, but there are also extrahepatic origins of C3 such as lymphoid macrophages. In the present study, the significance of C3 synthesis by bone marrow-derived cells was assessed by the transfer of wild-type bone marrow into irradiated C3-deficient mice. Using these chimeric mice, extrahepatic C3 was determined sufficient to initiate specific Ab and memory responses to a peripheral HSV-1 infection.

Animals↗
PubMed1997

Kinetics of blood component adsorption on poly(D,L-lactic acid) nanoparticles: evidence of complement C3 component involvement.

After intravenous administration, nanoparticles suffer a major drawback in that they are rapidly and massively taken up by the cells of the mononuclear phagocyte system. The mechanisms involved in the opsonization, adhesion, and internalization of biodegradable nanoparticles by the mononuclear phagocyte system are still poorly understood. In this work, the kinetics of blood protein adsorption onto nanoparticles of poly(D,L-lactic acid) prepared by the salting-out technique was investigated. Nanoparticles of 312 nm were incubated for variable periods of time (5-60 min) in human serum and citrated plasma. After incubation, the particles were washed and the proteins detached from them, denatured, and analyzed by two-dimensional polyacrylamide gel electrophoresis. In plasma, the predominant protein was immunoglobulin G (IgG), and the amount adsorbed was not dependent on incubation time. Albumin amounts were high for short incubation periods but decreased as a function of time, whereas apolipoprotein E levels increased significantly as a function of the incubation period. Owing to the possible complement cascade inactivation by addition of citrate to plasma, the kinetics of adsorption was also evaluated in serum. In this medium, adsorption of complement C3 components onto the surface of the nanoparticles was clearly evidenced by spots of increasing intensity and area, reaching levels comparable to those of the omnipresent IgG. This result confirms the important role of complement components in the opsonization process of poly(D,L-lactic acid) particles.

Adsorption↗
PubMed1992

Progesterone and RU486 regulation of uterine complement C3 after prior induction with estradiol.

Previous results demonstrated that progesterone (P4) given simultaneously with estradiol (E2) prevented stimulation by E2 of complement C3 expression in the immature rat uterus. Northern blot analysis revealed that simultaneous administration of P4 was able to prevent the E2-stimulated increase in C3 mRNA concentration in the luminal epithelial cells. The purpose of the present investigation was to determine whether progesterone modulates C3 expression after the gene has been induced by prior administration of E2 and also to determine the reversibility of this effect by the concomitant administration of RU38486, 17 beta-hydroxy-11 beta-[4-dimethylaminophenyl]estra-4,9,-dien-3-one (RU486). This regulation was studied by examination of protein synthesis as well as mRNA concentrations. Immature 21-day-old female rats were treated with E2 for 2 days (1 microgram/day), followed 24 h later by P4 (500 micrograms) or vehicle. Uteri were removed 6, 9, and 18 h after progesterone treatment and the radiolabeled secreted proteins were analyzed by SDS-PAGE and immunoprecipitation using a goat anti-rat C3 antibody. In animals treated with vehicle, E2-stimulated C3 synthesis remained elevated at 6 and 9 h and returned to control values by 18 h. In contrast, the administration of P4 resulted in a decrease in C3 synthesis at 6 and 9 h with the greatest decrease observed at 9 h. Similar results were obtained when C3 mRNA concentrations were examined. E2-stimulated C3 mRNA concentrations were decreased in rats treated with progesterone compared to those treated with vehicle alone.2

Animals↗
PubMed1997

TNF-alpha stimulates the biosynthesis of complement C3 and factor B by human umbilical cord vein endothelial cells.

The human umbilical cord vein (HUVEC) endothelial cells synthesize and secrete complement components. We analyzed the regulation of biosynthesis of the third component of complement (C3) and factor B (Bf) by cytokines in endothelial cells. Production of C3 increased after stimulation with TNF-alpha or IL-1beta and that of Bf with TNF-alpha, TNF-beta and IFN-gamma. TNF-alpha was the most effective in stimulating the secretion of C3 and Bf or the expression of mRNA of C3 or Bf. Preincubation with TNF-alpha for at least 36 or 24 h was needed for the stimulation, respectively. TNF-alpha, together with IFN-gamma had synergistic effects and the release of C3 or Bf increased to about 40- and 26-fold higher than those in control cells after incubation with both cytokines.

Cell Line↗
PubMed1987

Solution conformation of carboxy-terminal fragments of the third component of human complement C3: proton nuclear magnetic resonance study of C3a, des-Arg-C3a, and C3a Arg69.

A proton nuclear magnetic resonance (NMR) study is reported of the solution conformation of human C3a, that is released on activation of C3, the third component of complement. The intact C3a was used along with des-Arg-C3a, which is formed on cleavage of Arg-77 at the C terminal of C3a, and C3a Arg69, which is a 69-residue fragment produced on tryptic digestion of C3. A method of carboxypeptidase digestion/difference spectroscopy (Endo & Arata (1985) Biochemistry 24, 1561-1568) was extensively used for the spectral assignments of Ile-43, Ile-60, Leu-63, Tyr-15, and Tyr-59. On the basis of the results of nuclear Overhauser effect (NOE) measurements, we discuss the solution conformation of the C3a molecule. It has been concluded that removal of Arg-77, which is essential for expression of the biological activity of C3a, does not induce any significant change in the solution conformation of the C3a molecule. The C3a molecule is known to consist of a core region that comprises segment Tyr-15-Tyr-59. We conclude that in solution the C terminal segment sticks out of the core and takes on a helix-like conformation. Possible roles of the core region and the N terminal segment in maintaining the conformation of the C terminal segment are briefly discussed.

Amino Acid Sequence↗
PubMed2000

Molecular cloning and linkage analysis of complement C3 and C4 genes of the Japanese medaka fish.

The thioester-containing complement components, C3 and C4, are believed to have arisen by gene duplication from a common ancestor, and the mammalian C4 gene resides in the vicinity of the C2 and B genes within the major histocompatibility complex (MHC) class III region. To analyze the evolution of both the complement system and the MHC, we determined the complete primary structures of two C3 genes, termed Orla C3-1 and Orla C3-2, and one C4 gene, termed Orla C4, of a teleost, Japanese medaka fish (Oryzias latipes), by analyzing cDNA clones isolated from a liver library constructed using the inbred AA2 strain. The deduced basic structures of Orla C3-1, C3-2, and C4, such as the subunit chain structure, the thioester site, and the proteolytic activation site, are similar to their mammalian counterparts. However, the catalytic His residue which greatly increases the rate of thioester reaction, is replaced by Ala in Orla C3-2, implying functional differentiation between two C3 molecules. Mapping analysis revealed a close linkage between the C3-1 and C3-2 genes, indicating that they arose by a local duplication rather than by a genome-wide tetraploidization. The C4 gene belongs to a different linkage group, and no linkage was observed among the C3, C4, Bf/C2, MHC class I, and MHC class II loci. These results suggest that the MHC class III complement region was established in the tetrapod lineage, or lost in the teleost lineage.

Amino Acid Sequence↗