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PubMed1984

Anaphylatoxin-mediated regulation of human and murine immune responses.

C3a and C5a derived from the human complement components C3 and C5, respectively, were found to possess immunoregulatory activities. C3a was found to be capable of suppressing both antigen-specific and polyclonal antibody responses. In contrast, C3a was unable to suppress antigen- or mitogen-induced B or T cell proliferative responses. Helper T cells were found to be the target of C3a-mediated immunosuppression. Suppression occurred via the generation of suppressor T cells. In contrast to the results obtained with C3a, C5a was found to augment both antigen-specific and non-specific in vitro humoral immune responses. Moreover, C5a potentiated antigen- and alloantigen-induced T cell proliferative responses. As opposed to C3ades Arg-77, C5ades Arg retained all of the immunoregulatory activity associated with the intact molecule. Helper T cells are required for C5a-mediated potentiation of the Fc fragment-mediated polyclonal antibody response. Substitution for T cells by a soluble T cell-replacing factor rendered lymphocytes refractory to the enhancing properties of C5a.

Anaphylatoxins↗
PubMed1997

Structural definition of the C5a C terminus by two-dimensional nuclear magnetic resonance spectroscopy.

The serum glycoprotein C5a, which is derived from the proteolytic cleavage of complement protein C5, has been implicated in the pathogenesis of a number of inflammatory and allergic conditions. Because C5a induces an inflammatory response upon binding to a specific receptor, structural and mutagenesis studies were carried out to gain a better understanding of this binding interaction. These studies led to the first structural definition of the C terminus of recombinant human (rh)-C5a, determined by two-dimensional nuclear magnetic resonance (NMR) spectroscopy. Our results show that the C terminus adopts an alpha-helical conformation spanning residues 69 to 74, while the core domain exists as an antiparallel alpha-helical bundle. This C-terminal helix is connected to the core by a short loop that orients Arg 74 adjacent to Arg 62. Point mutation analysis had already revealed that residues 62 and 74 significantly contribute to agonist activity and receptor binding. Correlation of the C5a tertiary structure with mutational analyses clarifies the significance of the functional and binding properties of Arg 62 and suggests that both Arg 62 and Arg 74 interact at the same binding site on the receptor.

Amino Acid Sequence↗
PubMed1999

Complement-derived anaphylatoxin C5a protects against glutamate-mediated neurotoxicity.

Previous work from this laboratory indicates a role for the complement component C5 in neuroprotection against excitotoxicity. In the present study, we tested the hypothesis that the C5-derived anaphylatoxin C5a protects against kainic acid (KA)-induced neurodegeneration and investigated the mechanism of C5a neuronal activity in vitro. Brain intraventricular infusion of KA into adult mice caused neuronal morphological features of apoptosis in the pyramidal layer of the hippocampal formation as indicated by counts of neurons with pyknotic/condensed nuclei associated with cytoplasmic eosinophilia. Co-intraventricular infusion of human recombinant C5a with KA resulted in a marked reduction of morphological features of apoptotic neuronal death. In vitro studies confirmed C5a neuroprotection: treatment of primary murine corticohippocampal neurons with human or mouse recombinant C5a reduced glutamate neurotoxicity, as measured by trypan blue exclusion assay. This protection concurred with inhibition of glutamate-mediated induction of the caspase-3-related cysteine protease and coincided with marked reduction of neurons with morphological features of apoptosis, as found in vivo. Our studies indicate that C5a may inhibit glutamate-mediated neuronal death through partial inhibition of caspase-3 activity. These findings suggest a novel noninflammatory role for C5a in modulating neuronal responses to excitotoxins.

Alzheimer Disease↗
PubMed1985

Dimerization of human complement proteins C3 and C4 in dilute lauryl sulfate buffer after reaction with methylamine.

In the presence of methylamine and dilute lauryl sulfate (pH 8.0), the human C3 and C4 complement proteins dimerize almost completely. Under these conditions, the related complement protein C5 does not show any tendency to form dimers. This is shown by x-ray and neutron scattering at 9 degrees C and 0.15 M ionic strength. The radii of gyration of the C3 and C4 dimers are very similar, 7.7 and 7.4 nm, and the cross-sectional radii of gyration are the same, 3.4 nm. The scattering curves of the C3 and C4 dimers as well as their Fourier transforms, the p(r)-curves, can be explained by scattering from a model consisting of an elongated elliptic cylinder with semiaxes 6.5 and 2.1 nm and length of 23 nm. This elongated elliptic cylinder model is consistent with the elliptic cylinder model of C4 (Osterberg, R., Eggertsen, G., Lundwall, A., and Sjöquist, J. (1984) Int. J. Biol. Macromol. 6, 195-198) provided that the protein molecules dimerize via their cross-sectional surfaces. Also, the model is consistent with the model of the related protein, alpha 2-macroglobulin, where the four subunits are supposed to form pairwise dimers of an elliptic cylindrical form (Osterberg, R., and Malmensten, B. (1984) Eur. J. Biochem. 143, 541-544).

Buffers↗
PubMed1981

The chemotactic response of tumor cells. A model for cancer metastasis.

Injection of a C5-derived chemotactic factor for tumor cells into the peritoneal cavities of Sprague-Dawley rats induced diffuse mesenteric metastasis following the intravenous injection of Walker carcinosarcoma cells. Intraperitoneal injections of culture medium, histamine, or of trypsin-treated albumin resulted in many fewer metastases. Intraperitoneal injections of the chemotactic factor, unlike histamine, did not alter mesenteric vasopermeability as measured by the exudation of Evans blue into the mesentery. In vitro, tumor cells responded to the chemotactic factor by demonstrating directed migration in the Boyden chamber, by volume changes, measurable in the Coulter counter, and by demonstrating an increased adherence to nylon fibers. These phenomena are similar to the behavior of neutrophils in the presence of their chemotactic factors. All the responses in vitro were markedly depressed by the addition of 2-deoxyglucose, while the cell swelling response was slightly enhanced by cytochalasin B (again similar to the responses of leukocytes). The data suggest that movement of tumor cells from the circulation may be under chemotactic influence in the manner similar to the responsiveness of neutrophils to leukotactic stimuli in vivo.

Animals↗
PubMed2005

Terminal complement components mediate release of von Willebrand factor and adhesion of platelets in arteries of allografts.

BACKGROUND: Both humoral and cellular immune responses can cause arterial injury in organ transplants, but the manifestations of these different inflammatory mechanisms have not been dissected fully. The present study was designed to define the effects of the terminal complement components on arterial injury in vivo. METHODS: The authors have developed congenic rat strains with a C6 deficiency. The absence of C6 terminates the cascade of complement after C5 cleavage and prevents the assembly of the membrane attack complex. Hearts were transplanted from PVG.1A (RT1) rats to major histocompatibility complex-incompatible C6-deficient (C6-) or C6-sufficient (C6+) PVG.1U (RT1) rats. RESULTS: PVG.1A (C6-) cardiac grafts were rejected acutely (6-7 days) by untreated PVG.1U (C6+) recipients but survived significantly longer in PVG.1U (C6-) recipients (8 to >30 days). Arteries of cardiac allografts in C6+ recipients demonstrated extensive endothelial injury evidenced by release of von Willebrand factor (vWF) and accompanied by platelet aggregation. In contrast, vWF was retained in Weibel-Palade storage granules of arterial endothelial cells in cardiac allografts that were rejected by C6- recipients. In the absence of C6, intimal alterations were limited to lifting of endothelial cells from supporting stroma by infiltrating mononuclear cells, duplicating the clinical lesion described as endotheliitis or intimal arteritis. Delaying graft rejection with a short course of cyclosporine did not decrease vWF release and platelet aggregation in PVG.1U (C6+) recipients. CONCLUSIONS: Mononuclear cell infiltration of the arterial intima occurs in the absence of C6, but C6 deficiency limits the release of vWF from arterial endothelial cells.

Animals↗
PubMed1983

Demonstration of inflammatory mediator-induced inflammation and endothelial cell damage in the anterior segment of the eye.

Although some investigations have demonstrated the ability of inflammatory mediators, including vasopermeability and chemotactic factors, to induce acute inflammatory reactions in vivo, little is known about the response of various elements of the anterior segment to the direct effects of inflammatory mediators. These studies were initiated to develop models for the investigation of inflammatory responses in this region of the eye. Acute inflammatory reactions were induced within the rabbit anterior chamber by intracameral injection of 50 microliters of various inflammatory mediators and were evaluated by clinical grade, leukocyte influx into the aqueous humor, and morphologic changes in the corneal endothelium. Peak responses were recorded following injection of 10(-4) M formyl-methionyl-leucyl-phenylalanine (fMLP); 5 ED50 C5fr; 0.5 mg/ml C5; undiluted anti-red blood cell (RBC) serum; and 10(-5) M histamine. The number of leukocytes per milliliter of aqueous humor induced by each mediator was quantitated by comparison with the number of leukocytes induced by buffer instillation into a separate group of rabbits (mediator-induced influx/buffer-induced influx). Comparisons were made 24 hours after instillation of mediators. The results of these studies were as follows: buffer alone, 1.0; fMLP, 3.1 C5fr, 61.0; C5, 8.7; anti-RBC, 91.0; and histamine, 24.0. Clinical grades correlated well with these ratios. In addition, differences were noted when the time kinetics of acute responses induced by two different mediators (10(-4) M fMLP, a synthetic preformed chemotactic factor; and a 1:5 dilution of anti-RBC, which binds to vascular and corneal endothelial cells) were directly compared over 48 hours. Responses induced with fMLP peaked between 5 and 8 hours and resolved rapidly, whereas anti-RBC-induced responses peaked between 8 and 12 hours and resolved very slowly. Histopathologic analysis indicated that both fMLP and anti-RBC induced a similar sequence of changes in the corneal endothelium. Within 2-3 hours after instillation of either mediator, the endothelial cells exhibited prominent vacuolization/retraction phenomena. At the peak of leukocyte influx PMNs filled these vacuoles, then migrated back into the aqueous humor within several hours. Normal morphologic features were recovered following clearance of leukocytes from the anterior chamber. We believe that these models will be useful in identifying the roles of individual mediators in acute and chronic endocular inflammation and in the injury of corneal endothelium.

Animals↗
PubMed1978

Chemotactic factor influences on the aggregation, swelling, and foreign surface adhesiveness of human leukocytes.

Chemotactic factors have been shown to induce aggregation and cellular swelling of rabbit polymorphonuclear neutrophils (PMN) obtained from the peritoneum. We examined the ability of the chemotactic fragment of C5 and the synthetic chemotactic tripeptide formyl-methionyl-leucyl-phenylalanine to induce these changes in various preparations of human leukocytes. We found that these factors did induce dextran-sedimented leukocytes and Ficoll-Hypaque-isolated PMN to aggregate and swell. Compared with rabbit peritoneal PMN, however, human PMN responded with more prominent swelling but with less prominent aggregation. Also unlike rabbit peritoneal PMN, human PMN adhered spontaneously to plastic surfaces; the chemotactic factors enhanced this adherence. Certain similarities between the responses of these two cell types were evident: in both rabbit peritoneal and isolated human peripheral PMN, the aggregates had a short life span in the fluid phase; in both, the number of aggregates formed was proportional to the log10 of the PMN concentration; and, in both, the chemotactic activity of the reagents paralleled their aggregating activity. In the system employed, lymphocytes were unresponsive to the chemotactic factors. Ficoll-Hypaque-isolated mononoclear cells (containing varying proportions of monocytes and lymphocytes) were responsive, indicating that human monocytes behave in a manner similar to the human PMN. The results suggest that chemotactic factors induce responsive cells to develop a hyperadherent cytoplasmic membrane. Aggregation and increased adhesiveness to plastic surfaces may reflect this induction.

Animals↗
PubMed1977

Cleavage of human C5 by trypsin: characterization of the digestion products by gel electrophoresis.

Human C5 is composed of two nonidentical polypeptide chains, alpha and beta (m.w. 130,000 and 80,000, respectively) linked together by disulfide bonds and noncovalent forces. Cleavage of C5 by trypsin fragments with increased anodic mobilities. Limited digestion of C5 by trypsin (substrate to enzyme ratio 10:1 w/w at 37 degrees C for 1 min) resulted in the release of a small terminal alpha-chain peptide (alpha1, m.w. 15,000) probably analogous to C5a, from a large fragment, C5b (m.w. 195,000) composed of an intact beta-chain disulfide linked to an alpha-chain that has a lower m.w. (alpha' 115,000). Further digestion (37 degrees C, 5 min) resulted in cleavage of the alpha-chain at multiple sites with the production of three peptides from the alpha'-chain (alpha2I, 23,500; alpha2II 15,700 and alpha2III 10,200) and a residual fragment, C5c (m.w. 144,000). The alpha1 and alpha2 peptides are not covalently linked to the beta-chain nor to one another. The C5c fragment on the other hand is composed of small peptides of the alpha'c chain (alpha3 14,000; alpha4I 9,000; ALPHA 4II 11,000; alpha 5 23,000 to 30,000) which are linked to the beta-chain and also probably to one another by covalent bonds. Secondary cleavage occurred upon prolonged digestion with trypsin (37 degrees C, 20 min), and this resulted in the progressive erosion of the alpha'c peptides and the conversion of C5c to smaller C5c-like species.

Complement C5↗
PubMed1982

Biologic markers and breast cancer: a multiparametric study--1. Increased serum protein levels.

From early 1972 to the end of 1976, the profiles of several serum protein were used to monitor disease stage and prognosis of 207 patients with breast cancer. Six of these proteins, alpha 1-antitrypsin (alpha-AT), alpha 2-ceruloplasmin (Cp), beta 1-transferrin, IgA, C4, and C5, were significantly elevated in these cancer patients and were used as biologic markers in a multiparametric study. Among these breast cancer patients, 72% had at least two of these protein levels elevated, of which alpha-AT (55%), C5 (38%), and IgA (36%) levels were most commonly raised. The number of elevated proteins was parallel to disease progression as 61% (Group 1) and 74% (Group 2) of the patients with operable breast cancer and 90% of patients with metastatic disease showed an elevation of two or more of these nonspecific proteins. There was also a positive correlation between the number of elevated proteins and prognosis; of the 26 patients who died during the five-year follow-up, only four (15%) had no more than one protein level elevated, and 22 (85%) had two or more protein levels elevated. On the other hand, when considered as a group, patients with no or only one protein level elevated had a better prognosis than patients with two or more levels elevated (P less than 0.03). This multiparametric study tends to indicate that the high level of these serum proteins, reflecting an abnormal biochemical profile, provides valuable information that relates to the stage of the disease and patients' prognosis. Results also suggest that these proteins may aid in differentiating the group with high recurrent risks from that with a more favorable prognosis for a given clinical and pathologic stage, illustrating their importance as biologic markers in breast cancer.

Adult↗
PubMed2000

The C5a receptor is expressed in normal renal proximal tubular but not in normal pulmonary or hepatic epithelial cells.

C5a, a 74 amino acid peptide cleaved from the complement protein C5, is an extremely potent anaphylatoxin. Expression of the receptor for the anaphylatoxin C5a (C5aR) has been thought to be restricted to cells of myeloid origin. However, recent evidence suggests that the C5aR is also expressed in hepatocytes as well as in pulmonary epithelial, endothelial and smooth muscle cells. In the present study, we investigated the tissue distribution of C5aR by immunohistochemistry in normal human lung, liver, intestine and kidney using well-defined monoclonal antibodies (mAbs) directed against the extracellular N-terminus of the receptor. In all tissues examined, macrophages displayed an abundant expression of C5aR protein. However, in the normal human lung, C5aR expression was not detectable in bronchial and alveolar epithelial cells or in vascular smooth muscle or endothelial cells. In the normal human liver, no C5aR protein was detected in hepatocytes, whereas Kupffer cells strongly expressed the C5aR. In normal human kidney, the C5aR was detectable only in proximal tubular cells. C5aR gene transcription in Kupffer cells and proximal tubular cells was confirmed by in situ hybridization. Thus, our results point to an as yet unknown role of the C5aR in normal renal physiology. In the normal lung and liver, however, previous evidence for the ubiquitous expression of C5aR in epithelial, endothelial and smooth muscle cells in situ should be re-evaluated.

Antibodies, Monoclonal↗
PubMed2005

Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation.

Airway hyperresponsiveness and airway inflammation are hallmarks of allergic asthma, the etiology of which is crucially linked to the presence of Th2 cytokines. A role for the complement anaphylatoxins C3a and C5a in allergic asthma was suggested, as deficiencies of the C3a receptor (C3aR) and of complement factor C5 modulate airway hyperresponsiveness, airway inflammation, and Th2 cytokine levels. However, such models do not allow differentiation of effects on the sensitization phase and the effector phase of the allergic response, respectively. In this study, we determined the role of the anaphylatoxins on the effector phase of asthma by pharmacological targeting of the anaphylatoxin receptors. C3aR and C5a receptor (C5aR) signaling was blocked using the nonpeptidic C3aR antagonist SB290157 and the neutralizing C5aR mAb 20/70 in a murine model of Aspergillus fumigatus extract induced pulmonary allergy. Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade. Airway inflammation was significantly reduced in mice treated with the C3aR antagonist or the anti-C5aR mAb, as demonstrated by reduced numbers of neutrophils and eosinophils in bronchoalveolar lavage fluid. Of note, C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid. Cytokine levels of IL-5 and IL-13 in bronchoalveolar lavage fluid were not altered by C3aR or C5aR blockade. However, blockade of both anaphylatoxin receptors markedly reduced IL-4 levels. These data suggest an important and exclusive role for C5aR signaling on the development of airway hyperresponsiveness during pulmonary allergen challenge, whereas both anaphylatoxins contribute to airway inflammation and IL-4 production.

Animals↗
PubMed1996

Proteolytic inactivation of the leukocyte C5a receptor by proteinases derived from Porphyromonas gingivalis.

The anaerobic bacterium Porphyromonas gingivalis has been implicated as a primary causative agent in adult periodontitis. Several proteinases are produced by this bacterium, and it is suggested that they contribute to virulence and to local tissue injury resulting from infection by P. gingivalis. Cysteine proteinases with specificities to cleave either Arg-X or Lys-X peptide bonds (i.e., gingipains) have been characterized as predominant enzymes associated with vesicles shed from the surface of this bacterium. It has recently been demonstrated that these proteinases are capable of degrading the blood complement component C5, resulting in the generation of biologically active C5a. By using an affinity-purified rabbit antibody raised against residues 9 to 29 of the C5a receptor (C5aR; CD88), we demonstrate that noncysteinyl proteinases associated with vesicles obtained from P. gingivalis cleave the C5aR on human neutrophils. Proteolytic attack of the C5aR by enzymes from the P. gingivalis vesicles was inhibited by TPCK (tolylsullonyl phenylalanyl chloromethyl ketone), PMSF (phenylmethylsulfonyl fluoride), and dichloroisocoumarin, suggesting that serine proteinases are primarily responsible for this degradative activity. The purified vesicle proteinase Lys-gingipain but not Arg-gingipain also cleaved the N-terminal region of the C5aR on the human neutrophils. Lys-gingipain activity was essentially resistant to these inhibitors but was inhibited by TLCK (Nalpha-p-tosyl-L-lysine chloromethyl ketone) and iodoacetamide. A synthetic peptide that mimics the N-terminal region of C5aR (residues 9 to 29; PDYGHY DDKDTLDLNTPVDKT) was readily cleaved by chymotrypsin but not by trypsin, despite the presence of two potential trypsin (i.e., lysyl-X) cleavage sites. The specific sites of cleavage in the C5aR 9-29 peptide were determined by mass spectroscopy for both chymotrypsin and Lys-gingipain digests. This analysis demonstrated that the C5aR peptide is susceptible to cleavage at both potential Lys-gingipain sites (i.e., between residues 17 and 18 [K-D] and 28 and 29 [K-T]) and at two chymotrypsin sites (between residues 14 and 15 [Y-D] and 20 and 21 [L-D]), respectively. These studies suggest that P. gingivalis contains at least two enzymes capable of cleaving the C5aR, Lys-gingipain and a second nontryptic serine proteinase that is distinct from either Arg- or Lys-gingipain.

Amino Acid Sequence↗
PubMed1988

Monocyte retention and migration in pulmonary inflammation. Requirement for neutrophils.

The acute inflammatory process is characterized by an orderly progression of events; an initial phase of early neutrophil accumulation and a later phase of mononuclear cell (including monocyte) accumulation. The mechanisms which control the transition from one phase to the other are largely unknown. We present a rabbit model of C5 fragment (C5f)-induced lung inflammation in which purified radiolabeled peripheral blood neutrophils and monocytes were used as probes to monitor the retention and emigration of these leukocytes into well localized areas of inflammation. Neutrophil preparations (greater than 95% pure) were isolated by discontinuous plasma-Percoll density gradients, and monocyte preparations (greater than 91% pure) were isolated by counterflow cell elutriation, labeled with 111Indium-tropolonate, and intravenously infused into separate recipient animals. The monocytes circulated with a half-life of approximately 30 hours. The retention of labeled monocytes or neutrophils within the lung was monitored scintigraphically. C5f-induced monocyte lung retention was delayed 2 to 4 hours compared with neutrophil lung retention. Radiolabeled neutrophils were selectively retained in the area of C5f-induced inflammation (right cranial lung lobe, RCL) as early as 20 minutes after the induction of the inflammatory response, reached a maximum by 2 hours, and were not retained by 48 hours after C5f instillation. The signal inducing C5f-induced monocyte lung retention was shown to be transient. Monocytes were selectively retained in the RCL if the area of inflammation was induced 2 to 4 hours but not 15 minutes or 16 hours before their infusion. The time course of C5f-induced monocyte migration into the alveolar space determined by lavage analysis was delayed 2 to 3 hours compared with neutrophil migration. Neutrophils selectively migrated into the RCL 1 to 2 hours after the induction of the inflammatory response, reached a maximum by 4 hours, and had disappeared by 48 hours. Radiolabeled monocytes selectively migrated into the RCL 3 to 4 hours after the induction of the inflammatory response, reached a maximum by 4 hours, and remained present through 48 hours. The total number of labeled and unlabeled mononuclear cells present in the C5f-treated RCL lavage at 48 hours was significantly increased above controls. The signal for this monocyte migration (as for lung retention) was shown to be transient in that radiolabeled monocytes did not migrate when infused 16 hours after the induction of the inflammatory response. C5f did not induce monocyte lung retention nor monocyte migration into the alveolar space of animals rendered neutropenic.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1981

Induction of ocular inflammation by synthetic mediators.

Chemotactic mediators, N-formylmethionyl-leucyl-phenylalanine (FMLP) and the complement component C5a, were injected into the rabbit cornea, vitreous, and skin to induce a reaction resembling the "Arthus phenomenon." Injection of these mediators induced edema and granulocytic infiltration in the cornea, conjunctiva, and skin. These histologic changes resembled the inflammation produced by antigen (ovalbumin [OVA]) in specifically immunized rabbits. Keratitis began after two hours and subsided six hours after the injection. Conversely, the vitreous response started six hours after injection of FMLP and C5a and peaked between 24 and 48 hours. All the inflammatory reactions induced by FMLP, C5a, and rechallenge with antigen could be inhibited in varying degrees by subconjunctival injection of 0.1 mL of 10(-5)M dexamethasone, quinacrine, 5,8,11,14-eicosatetraynoic acid (ETYA), or indomethacin, agents that suppress different sites of chemotaxis of polymorphonuclear leukocytes. However, only the inflammation induced by FMLP could be inhibited by carbobenzoxy-phe-met, a competitive inhibitor of FMLP.

Animals↗
PubMed1989

Pristane-induced arthritis. The immunologic and genetic features of an experimental murine model of autoimmune disease.

Pristane was injected intraperitoneally into mice of several strains, inducing an inflammatory seropositive arthritis in susceptible strains. The evolving histologic features included synovial hyperplasia, periostitis, and progressive marginal erosions. Multiple serologic immune abnormalities, including rheumatoid factor and anticollagen antibodies, also developed. Genetic analysis indicated that the major histocompatibility complex (H-2), C5 hemolytic complement (Hc), Newcastle disease virus-induced interferon (IF-1), and athymic (nu/nu) loci were involved in regulating susceptibility to pristane-induce arthritis. This experimental murine disease may provide a novel model of rheumatoid arthritis.

Animals↗
PubMed1982

Superoxide anion generation by human neutrophils exposed to monosodium urate.

We studied the capacities of naked and protein-coated monosodium urate (MSU) crystals to stimulate superoxide anion (O(2)) release by human polymorphonuclear leukocytes (PMN). Uncoated MSU estimated significant O(2) production by cytochalasin B-treated PMN. Precoating MSU with IgG caused an increase in mean O(2) production, whereas precoating heated MSU with serum or plasma inhibited O(2) release. Unheated MSU crystals, which activate complement to a greater extent than heated crystals, also provoked O(2) generation, an effect again abrogated by precoating with serum but not with plasma. Coincubation of unheated MSU and plasma resulted in an enhancement of O(2) generation. The results of these experiments support the hypothesis that adsorbed proteins modulate the phlogistic potential of MSU and that the surface activation of humoral mediators contributes to the local inflammatory response.

Adsorption↗