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PubMed1992

Induction of C3 expression in astrocytes is regulated by cytokines and Newcastle disease virus.

Synthesis of complement proteins and their regulation in resident cells of the central nervous system are important pathophysiologic factors that can affect the outcome of inflammatory central nervous system diseases. Primary cultures of rat astrocytes constitutively express C3 mRNA and produce C3 protein; both of them were enhanced by LPS or by a live as well as inactivated Newcastle disease virus, a neurotropic paramixovirus. TNF, IL-1 beta, and IL-8 also increased the levels of C3 mRNA and protein whereas IL-1 alpha and IL-6 had no effect, although all of these cytokines are inducible by LPS. LPS stimulation in the presence of cycloheximide decreased the LPS-mediated C3 mRNA induction by 60%. These data suggest that LPS effect on C3 regulation is mediated directly by LPS as well as by LPS-induced cytokines. Interestingly, C3 mRNA induced by Newcastle disease virus or inactivated Newcastle disease virus was inhibited by protein kinase inhibitors, H-7 and staurosporine, whereas these inhibitors had no effect on C3 induction mediated by LPS or cytokines, indicating the existence of different signal transduction pathways.

Alkaloids↗
PubMed1984

C-reactive protein inhibits pneumococcal activation of the alternative pathway by increasing the interaction between factor H and C3b.

We previously studied two alternative pathway activators, Streptococcus pneumoniae and positively charged liposomes, which react with C-reactive protein (CRP). Binding of CRP to these surfaces initiates classical pathway but blocks alternative pathway activation. In this study, we investigated the mechanism of this inhibition using S. pneumoniae, R36a. R36a were pretreated with CRP (CRP-R36a) or buffer and incubated with C2-deficient human serum to which 125I-labeled C3 had been added. The amount of specific 125I-C3 binding was decreased from 8200 mol/CFU on R36a to 2200 mol/CFU on CRP-R36a. In contrast, when the same experiment was performed with purified factors B, D, P, and C3, in the absence of regulatory proteins, specific 125I-C3 uptake was slightly lower on R36a (6100 mol/CFU) than on CRP-R36a (8100 mol/CFU). The ability of the fixed C3b to inactivate factor B in the presence of factor D was equivalent on the two surfaces. The binding of the regulatory factor H to C3b fixed to R36a and CRP-R36a was compared by using purified 125I-labeled factor H. The ratio of factor H bound to C3 bound was twofold greater on CRP-R36a than on R36a. This increase was found by using C2-deficient serum or purified factors B, D, P, and C3 to fix C3b to the surfaces. The ability of CRP to inhibit C3 binding to R36a was restored by the addition of factors H and I to factors B, D, P, and C3. These results indicate that CRP inhibits alternative pathway activation by increasing regulation of bound C3.

Binding, Competitive↗
PubMed1983

Interaction of C4-binding protein with cell-bound C4b. A quantitative analysis of binding and the role of C4-binding protein in proteolysis of cell-bound C4b.

Purified C4-binding protein (C4-bp) was shown to bind to cell-bound C4b by radioactive tracer techniques. With EAC4 bearing greater than 3,000 C4b-molecules/cell, the number of C4-bp molecules bound was directly proportional to the number of C4b molecule on the cell surface; EAC4 bearing less than 3,000 C4b-molecules/cell bound a very small amount of C4-bp. Scatchard analysis of binding of C4-bp indicated an equilibrium constant of 4.6 X 10(8) L/M and a maximum of 0.43 C4-bp molecules bound per C4b molecule, equivalent to an average of one molecule of C4-bp per two or three molecules of C4b. Fluid-phase C4b inhibited the binding of C4-bp to cell-bound C4b in a dose-dependent manner, whereas native C4 had little effect. C2 inhibited this binding and also released C4-bp from EAC4,C4-bp. However, C2 was 27 times less effective than unlabeled C4-bp on a molar basis and a considerable amount of C4-bp remained bound to C4b on the cell surface even in the presence of a large excess of C2. We also examined the cofactor activity of C4-bp in the cleavage of cell-bound C4b by C3b/C4b inactivator (I). Cleavage of the alpha' chain of C4b on the cell surface by I alone was incomplete and an intermediate cleavage product, alpha-75, was observed. When C4-bp bound to C4b on the cell surface, the alpha' chain of the C4b cleaved into three fragments, alpha 2, alpha 3, and alpha 4. The alpha 3, alpha 4, beta, and gamma peptides (C4c) were released into the fluid phase, and the alpha 2 fragment (C4d) remained linked covalently to the cell membrane via an ester bond. In some situations, therefore, C4-bp enhances the proteolytic activity of I on cell-bound C4b.

Animals↗
PubMed2006

Complement escape of human pathogenic bacteria by acquisition of complement regulators.

Pathogenic micro-organisms employ a broad range of strategies to survive in and to persistently infect the human host. Far from being completely understood by which highly sophisticated means invading pathogens overcome the host's destructive immune defence, there is a growing body of evidence on particular mechanisms which play a pivotal role for immune evasion. This review focuses on evasion of medically and scientifically important bacteria by acquisition of host derived fluid-phase complement regulatory proteins, in particular factor H, FHL-1, and C4b binding protein. Expression of microbial surface molecules binding to human complement regulators and thus fixing them in a functionally active state allows pathogens to inhibit and finely regulate complement activation directly on their surface. Further studies on the utilization of host complement regulatory proteins will likely have a marked impact on a more efficient and specific clinical treatment.

Bacteria↗
PubMed1983

Inherited disorders of complement.

Isolated complement component deficiencies are uncommon. Deficiencies of all eleven components and two inhibitors of the classical pathway have been described. Complete absence of the components of the alternative pathway has not been described. The consequences of a single defect in complement are often predictable from an understanding of the biologic activities associated with activation of the complement system. Deficiency of C1 esterase inhibitor gives rise to the disease, hereditary angioedema; deficiency of the early components of the classical pathway are associated with lupus erythematosus; C3 and C3 inactivator deficiencies with pyogenic infections; C5 dysfunction with Leiner's disease; deficiencies of the terminal components with recurrent Neisseria bacteremia; and C9 deficiency with normal health. The complement system and its associated biologic activities are reviewed. The present knowledge of the inherited complement deficiencies and associated diseases, with particular emphasis on the dermatologic manifestations, genetics, and diagnosis, is summarized.

Angioedema↗
PubMed2004

Cyclic AMP-mediated upregulation of the expression of neuronal NO synthase in human A673 neuroepithelioma cells results in a decrease in the level of bioactive NO production: analysis of the signaling mechanisms that are involved.

The expression level of neuronal nitric oxide synthase (nNOS) can vary depending on the (patho)physiological conditions. Here we document a marked induction of nNOS mRNA, protein, and total NO production in response to dibutyryl cyclic AMP (db-cAMP) in human A673 neuroepithelial cells. However, the upregulation of nNOS was associated with a decreased level of production of bioactive NO and by an increase in the level of generation of reactive oxygen species (ROS). ROS production could be prevented by the NOS inhibitor L-NAME, suggesting nNOS itself is involved in ROS generation. Sepiapterin supplementation of db-cAMP-treated A673 cells could restore full bioactive NO production, most likely by preventing the uncoupling of nNOS. nNOS was upregulated by other stable analogues of cAMP, by the activator of adenylyl cyclase forskolin, by isoproterenol or by dopamine through activation of D1 receptors, and by inhibitors of phosphodiesterase. cAMP did not change the half-life of the nNOS mRNA. Inhibitors of protein kinase A (PKA), H-89 and R(p)-cAMPS, produced a partial inhibition of basal and cAMP-induced nNOS expression. cAMP response element binding and modulator transcription factors (CREB and CREM), typical target proteins of PKA, were expressed in A673 cells, as was the coactivator CREB binding protein (CBP). cAMP-stimulated induction of nNOS was significantly enhanced in A673 cells stably transfected with wild-type CREB and almost abolished in cells transfected with KCREB (containing a mutation of the DNA binding domain). In A673 cells transfected with CREB(133) (containing a mutation of the phosphorylatable serine 133), the overall level of nNOS expression was reduced, but the expressional stimulation by cAMP remained. This suggests that CREB bypasses, in part, the classical requirement for phosphorylation and association with CBP. Three members of the recently described four-and-a-half-LIM-domain proteins (FHL1-FHL3) were found to be expressed in A673 cells; FHL-1 and FHL-3 were upregulated by cAMP. These proteins can provide direct activation function to both CREB and CREM, and may be responsible for the PKA-independent component of CREB and CREM activity.

Animals↗
PubMed1983

Enzymic assay of C3b receptor on intact cells and solubilized cells.

The C3b receptor of human erythrocytes is known to act as a cofactor for the cleavage of the complement protein C3b by the serine proteinase C3b/C4b Ina. The same cofactor activity is shown to be present on human tonsil B-lymphocytes. The cofactor activity of the C3b receptor can be assayed, on intact cells or in solubilized extracts of cells, by determining the rate of C3b cleavage in the presence of fixed concentrations of C3b and of C3b/C4b Ina. This assay method was used to compare the characteristics and relative quantities of C3b receptors on erythrocytes and lymphocytes. The cofactor activities associated with these two cell types resemble each other, but are distinct from the serum cofactor proteins, C4bp and Factor H, in antigenicity and in pH- and ionic-strength-dependence, and are distinct from Factor H in substrate specificity. Assay of cofactor activity in intact cells indicates that there are about 80-fold more receptors per cell on the lymphocyte surface than on erythrocytes. Assays with cells made permeable by detergent show that, whereas essentially all of the receptors on erythrocytes are on the cell surface, B-lymphocytes contain a large internal receptor pool, which makes up more than 80% of the total cofactor activity of the cell.

B-Lymphocytes↗
PubMed1986

Primary structure of human complement component C2. Homology to two unrelated protein families.

The primary structure of the second component of human complement (C2) was determined by cDNA cloning and sequence analysis. C2 has 39% identity with the functionally analogous protein Factor B. The C-terminal half of C2a is homologous to the catalytic domains of other serine proteinases. C2b contains three direct repeats of approx. 60 amino acid residues. They are homologous to repeats in Factor B, C4b-binding protein and Factor H, suggesting a functional significance of the repeat in C4b and C3b binding. The repeats are also found in the non-complement proteins beta 2-glycoprotein I and interleukin-2 receptor, and this repeat family may be widespread.

Amino Acid Sequence↗
PubMed1991

Anti-inflammatory and immunosuppressive effects of recombinant soluble complement receptors.

CR1 and CR2 have served as unusual probes for the analysis of the two major functions of the immune system involving inflammation and the immune response, respectively. CR1, or some construct containing its active site SCRs, may find a role in the therapy of complement-dependent tissue injury, and may be used to define which diseases are caused by the inappropriate or excessive activation of this system. Although soluble forms of CR2 may be shown to have potential clinical utility when foreign antigen is given prospectively, as in monoclonal antibody therapy, perhaps the most important finding emanating from the analysis of this receptor is the recognition of a previously unrecognized membrane protein complex whose role in B cell development is yet to be determined. It is reasonable to predict that the function of the CD19 complex will be significant as it serves as the link between two evolutionarily distinct systems that share a common purpose of anti-microbial host defense.

Animals↗
PubMed1999

Regulation of complement activation by C-reactive protein: targeting the complement inhibitory activity of factor H by an interaction with short consensus repeat domains 7 and 8-11.

C-reactive protein (CRP) is a major acute phase protein whose functions are not totally clear. In this study, we examined the interaction of CRP with factor H (FH), a key regulator of the alternative pathway (AP) of complement. Using the surface plasmon resonance technique and a panel of recombinantly expressed FH constructs, we observed that CRP binds to two closely located regions on short consensus repeat (SCR) domains 7 and 8-11 of FH. Also FH-like protein 1 (FHL-1), an alternatively spliced product of the FH gene, bound to CRP with its most C-terminal domain (SCR 7). The binding reactions were calcium-dependent and partially inhibited by heparin. In accordance with the finding that CRP binding sites on FH were distinct from the C3b binding sites, CRP preserved the ability of FH to promote factor I-mediated cleavage of C3b. We propose that the function of CRP is to target functionally active FH and FHL-1 to injured self tissues. Thereby, CRP could restrict excessive complement attack in tissues while allowing a temporarily enhanced AP activity against invading microbes in blood.

Binding Sites↗
PubMed1985

Generation of the bioactive kallikrein-derived fragment, C3d-k, by HANE-plasma.

Recent studies have concluded that after complement activation the final physiologic degradation products of C3 are C3c and the fragment of relative molecular mass (Mr) 42,000 which contains the C3d and C3g domains and was therefore named C3d,g. Using fluorescent labelled C3b as a substrate, we have determined the putative C3d,g ('C3d,g') producing activity of both normal and hereditary angioneurotic oedema (HANE) plasmas. In normal plasmas, the rate of production of C3d,g was 1.0 +/- 0.2 X 10(-10) mol/ml/h and this activity was blocked by antibodies to I. In contrast, HANE, plasmas (deficient in C1INH) showed more than twice as much 'C3d,g' production as normal plasmas and both antibodies to I and kallikrein were required to inhibit this activity. Because of this result, a more sensitive gel system was employed to detect the Mr 42,000 peptide and two 'C3d,g' fragments of approximately equal intensity with Mr of 42,000 and 43,000 were defined. Incubation of purified kallikrein with labelled iC3b produced a C3d,g-like fragment, C3d-k, that aligned with the band of 43,000 Mr generated in HANE plasma. These results indicate that HANE plasma, in contrast to normal plasma, generates the bioactive C3d-k fragment. C1INH blocks the activities of kallikrein and C1s, and C3d-k generation in HANE plasma is probably secondary to the proteolytic activity of kallikrein.

Angioedema↗
PubMed1981

Deposition of C4-binding protein and beta 1H globulin in kidneys of patients with IgA nephropathy.

A study on the deposition of complement control proteins in renal tissues from patients with IgA nephropathy is described. Renal biopsy specimens were obtained from patients with IgA nephropathy and other glomerular diseases. These biopsy samples were stained with antisera to human C4-binding protein and beta 1H globulin by indirect immunofluorescent staining. It was shown that the complement system is activated in IgA nephropathy via the both alternative and classical pathways.

Carrier Proteins↗
PubMed1982

Complement: activation, consequences, and control.

The activation of complement provides the humoral (fluid-phase) effector mechanism most responsible for immune-mediated injury. The classical pathway is activated by an antigen-antibody reaction. The binding of C1q initiates the sequential activation of the eleven proteins. The classical pathway has a calcium-dependent step (C1q, C1r, C1s) and a magnesium-dependent reaction (the enzymatic action of C1s on C4 and C2). The alternative pathway appears to be spontaneously activated, but the perpetuation of that activation is dependent upon the availability of an activating (or protective) surface which interferes with the inactivation of C3b by control proteins. The alternative pathway has a magnesium-dependent step, the binding of B to C3b to form the C3 convertase. Once initiated, the alternative pathway activation results in the sequential activation of nine proteins, six of which are common to both pathways. The activation of complement results in a variety of biologic consequences which can result in injury to the host. The potential destructiveness of the effects of complement activation is modulated by a series of control proteins.

Carrier Proteins↗
PubMed1981

Solubilization of immune precipitates by six isolated alternative pathway proteins.

Immune precipitates were solubilized by the alternative pathway of complement assembled from isolated proteins, i.e., C3, factor B, factor D, properdin, C3b inactivator (C3bINA), and beta 1H. The kinetic curves of solubilization in the isolated system and in EGTA-serum were virtually indistinguishable. No requirement of other factors was apparent. Deletion of C3bINA and beta 1H from the complete mixture caused total consumption of C3 in the fluid phase and resulted in neither C3 binding to the complexes nor solubilization. Thus, the presence of a regulated fluid-phase reaction is essential for efficient fixation of C3 and the consequent solubilization. In addition, properdin plays an essential role in the complement-mediated solubilization in the presence of the two regulators. A large amount of C3 was incorporated into the antigen-antibody lattice. Solubilization of immune complexes started after the binding of one C3 molecule to one antibody molecule in the complexes, and the molar ratio of C3:antibody in the solubilized complexes also is approximately 1.

Animals↗
PubMed1984

Regulatory proteins for the activated third and fourth components of complement (C3b and C4b) in mice. I. Isolation and characterization of factor H: the serum cofactor for the C3b/C4b inactivator (factor I).

Factor H, purified from mouse EDTA-plasma using a 4-step procedure, consists of a single polypeptide chain of Mr 150,000 on SDS-PAGE. Mouse H (Hmo) was required for the cleavage of fluid-phase mouse C3b by mouse I (Imo). The final product of degradation of fluid-phase mouse C3b was iC3b, consisting of fragments of the alpha'-chain (alpha'-70, alpha'-43) linked by disulfide bonds to an intact beta-chain. Imo alone was capable of cleavage of membrane-bound mouse C3b and of generating iC3b. The addition of Hmo nevertheless had an enhancing effect on Imo activity, but cleavage did not proceed beyond iC3b. These observations suggest that one important function of Hmo is to permit the inactivation of fluid-phase C3b, and to inhibit irreversibly its activity. The concentration of H in the plasma of male and female BALB/c mice was not significantly different. Among different inbred strains of mice, large differences were observed in the plasma levels of H, and plasma H levels were positively correlated with the plasma levels of C3. This observation, taken together with the well known role of H in the control of the activation of the alternative pathway, suggests that the turnover of C3 is controlled to some extent by H.

Animals↗