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PubMed1983

An improved fluorogenic substrate for the alternative complement pathway C3/5 converting enzyme CVFBb.

By lengthening the sequence of a previously available tripeptide to a pentapeptide, we were able to increase the specificity of the substrate for the complement enzyme CVFBb (EC 3.4.21.47) over Factor Xa (EC 3.4.21.6). This increase in specificity was achieved by both an increase in the kcat/Km for CVFBb for the longer substrate compared to the original substrate, and a decrease in the kcat/Km for Factor Xa. The new substrate, Boc-Nle-Gln-Leu-Gly-Arg-amino methyl coumarin (AMC) was synthesized by coupling Boc-Nle-Gln-Leu-Gly to Arg-AMC in solution. p-Toluenesulfonic acid was added to the coupling mixture to improve the solubility of the arginine derivative and avoid the need for covalent protection.

Chromatography, High Pressure Liquid↗
PubMed1986

Growth-supporting activity of fragment Ba of the human alternative complement pathway for activated murine B lymphocytes.

We have investigated the effects of cleavage of factor B by its activating enzyme, factor D, as well as its activation fragments Bb and Ba, on the growth of mouse spleen B lymphocytes preactivated by LPS. Neither factor B nor factor D show any growth-supporting activity when tested alone. The coaddition of factor B and factor D to serum-free cultures of LPS-preactivated B cell blasts increased the proliferation of the responding cells up to the level obtained by restimulation with LPS. Such growth-supporting activity was shown to be mediated by Ba, whereas Bb did not show any significant effect. Furthermore, this effect was not restricted to the LPS-preactivated B cell blasts; in fact, Ba also supported the growth of in vivo, activated B cell blasts of unprimed mice of the LPS-nonresponder C3H/HeJ strain. In contrast, Ba did not maintain growth of Con A-activated T cells or TCGF-dependent CTL cells. Taken together, these results describe the first biological activity of human Ba as a B cell stimulatory factor.

Animals↗
PubMed1997

Alternative pathway complement activation induces proinflammatory activity in human proximal tubular epithelial cells.

BACKGROUND: Proximal tubular epithelial cells express a surface C3-convertase activity which induces C fixation and insertion of the C5b-9 membrane attack complex (MAC) into the cell plasma membrane. The physiopathological consequences of this phenomenon are unknown. METHODS: The effect of C fixation on the production of inflammatory mediators by human proximal tubular epithelial cells in culture was explored. RESULTS: Proximal tubular epithelial cells incubated with a sublytic amount of normal human serum as a source of C, but not with heat-inactivated human serum, showed a time-dependent calcium influx and a concomitant release of 14C-arachidonic acid (14C-AA). Eicosanoid synthesis following the arachidonic acid mobilization was studied as prostaglandin E2 release. Mg2+/EGTA, which did not prevent C activation by the C3-convertase, and p-bromodiphenacyl bromide a phospholipase A2-inhibitor, inhibited mobilization of 14C-AA. These results suggest the activation of an extracellular Ca(2+)-dependent, phospholipase A2. Complement fixation was associated with the synthesis of proinflammatory cytokines such as IL-6 and TNF-alpha. Experiments with C6-deficient sera indicated that the release of 14C-AA and the production of cytokines were dependent on the insertion of the terminal components of complement in the plasma membrane. Indeed, the reconstitution of normal haemolytic activity of C6-deficient sera with purified C6 restored also the release of 14C-AA and the production of cytokines. CONCLUSIONS: In vitro complement activation on the proximal tubular cell surface triggers the generation of proinflammatory mediators, which may potentially contribute to the pathogenesis of tubulointerstitial injury.

Arachidonic Acid↗
PubMed1984

Enhanced prothrombin-converting activity and factor Xa binding of platelets activated by the alternative complement pathway.

Platelet prothrombin-converting activity and factor Xa binding were studied after exposure of human platelet rich plasma (PRP) to various conditions leading to platelet activation. Zymosan resulted in increased platelet-bound C3, enhanced prothrombin-converting activity and increased factor Xa binding. Similar findings were observed with normal platelets resuspended in factor XII-deficient plasma. The combined use of zymosan and thrombin to activate platelets resulted in synergistic prothrombin-converting activity and factor Xa binding. In contrast, no synergism was obtained with the concomitant use of zymosan and collagen, suggesting that collagen and zymosan share the same pathway for platelet activation. Heterologous antibody to factor V completely inhibited the platelet prothrombin-converting activity for all modes of platelet activation, indicating that this activity is mediated by factor V.

Blood Platelets↗
PubMed1987

Effects of lysine and glutamic acid or [corrected] Mg++ on the conformations of C3 and B, and the activation of the alternative complement pathway.

The conversion of C3 and B in the mixture of C3, B, D and Mg++ ions was inhibited in the presence of arginine and lysine, but not in the presence of glutamic acid and aspartic acid among other amino acids. Application of dialyzed plasma to a lysine-Sepharose column resulted in elution of B and a part of D in pass-through fractions, and C3 and the other part of D were retained in the column, subsequently eluted by increase in salt concentrations. C3, B and a part of D were eluted in pass-through fractions, and C3 and the other part of D were retained in the column, subsequently eluted by increase in salt concentrations. C3, B and a part of D were eluted in pass-through fractions when applied to glutamic acid-Sepharose. A highly purified D preparation appeared in the pass-through fraction of the lysine-Sepharose column, suggesting that D may form a complex in plasma. The intensity of intrinsic fluorescence of C3 decreased in the presence of arginine to the largest extent. Lysine affected the intensity less than arginine. Kd was calculated to be 0.42 mM for arginine and 0.55 mM for lysine in the interaction with C3. The intensity of intrinsic fluorescence of B decreased in the presence of aspartic acid and glutamic acid (Kd = 0.48 mM for aspartic acid and 0.24 mM for glutamic acid). Arginine or lysine affected the intensity of B less than those anionic amino acids. The presence of Mg++ ions resulted in a decrease in the fluorescence intensity of C3 and B.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1990

Antiinflammatory effects of polypeptide growth factors. Platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor inhibit the cytokine-induced expression of the alternative complement pathway activator factor B in human fibroblasts.

The synthesis of complement components in human fibroblasts is modulated by mediators of inflammation such as cytokines. In particular, interleukin-1 (IL-1) and tumor necrosis factor (TNF) induce time- and dose-dependent increases in the synthesis of complement proteins factor B (FB), C3, and factor H (FH). Polypeptide growth factors are also soluble mediators released during inflammation and able to modulate many fibroblast functions. We have studied the effects of polypeptide growth factors platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) on the synthesis of complement proteins in cultured human fibroblasts. PDGF, EGF, and FGF alone did not affect the level of synthesis of any of the complement proteins analyzed, but simultaneous incubation of PDGF, EGF, or FGF with IL-1 and TNF resulted in a dose-dependent inhibition of the cytokine-enhanced expression of FB. Inhibition of FB synthesis was observed between 4 and 8 h of exposure to PDGF and persisted for 4 h after the removal of the growth factor. Analysis of steady-state levels of specific FB mRNA suggested that PDGF-induced inhibition of FB synthesis is mediated at a pretranslational level and that it requires new protein synthesis. The effect of the growth factors was limited to FB, with marginal or no inhibition on the cytokine-enhanced synthesis of C3 and FH, excluding the possibility that the inhibitory effects of PDGF, EGF, and FGF on FB synthesis were due to a negative modulation of the growth factors on cytokine cell membrane receptors. Specific inhibition of cytokine-induced increases in FB synthesis by the growth factors may represent down regulation of the acute inflammatory process, further permitting progression to processes of tissue repair and remodeling. Study of the interactions between cytokines and growth factors in the regulation of synthesis of complement proteins may also provide a system for investigating mechanisms of signal transduction of both polypeptide growth factors and cytokines.

Anti-Inflammatory Agents, Non-Steroidal↗