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PubMed1982

Production of cyclooxygenase products and superoxide anion by macrophages in response to chemotactic factors.

Mononuclear phagocytes are known to play a key role in various phlogistic reactions by synthesizing and releasing products that may potentiate or inhibit inflammatory processes. The expression of these products appears to be dependent on the source of the macrophage population as well as the stimulus employed. We have studied superoxide anion (O-2) production as well as the generation of PGE2, PGF2 alpha, and TXB2 from resident, oil-elicited and thioglycollate-induced peritoneal macrophages in mice in the presence and absence of chemotactic peptides. Production of O-2, occurred only in elicited macrophages stimulated with high concentrations of FMLP or C5a; resident cells stimulated with either of the chemotactic peptides were completely unresponsive. Although resident peritoneal macrophages incubated with chemotactic peptides did not generate O-2, these cells did secrete significant levels of PGE2, PGF2 alpha, and TXB2 in response to C5a. FMLP had no stimulatory effect. Elicited macrophages generated increased levels of PGE2 and PGF2 alpha when incubated with C5a. However, production of TXB2 was not stimulated. FMLP was inactive in stimulating PGE2, PGF2 alpha, and TXB2 in all types of macrophages studied. These studies indicate a heterogeneity in the production of inflammatory mediators from various macrophage populations in response to chemotactic factors.

Animals↗
PubMed1988

Atopic dermatitis: influence of bacterial infections on human monocyte and neutrophil granulocyte functional activities.

In 15 patients with atopic dermatitis (AD) and without concomitant viral or bacterial infections, chemotaxis, superoxide-anion (O2-) generation, and beta-glucuronidase release of purified monocytes (MO) and neutrophils (PMN) were determined. Defined receptor-dependent stimulators (i.e., N-formyl-methionyl-leucyl-phenylalanine, C5a, and leukotriene B4, as well as native and opsonized zymosan particles) were used for phagocyte stimulation. PMN functional activities in response to the stimuli tested were found to be normal in patients with AD and without infections. MO from these patients revealed a slight enhancement of O2- production after stimulation with opsonized zymosan and a small increase of N-formyl-methionyl-leucyl-phenylalanine-induced chemotaxis. Other MO functions tested were within the normal range. However, investigations of MO and PMN functions during the course of concomitant bacterial infections of three patients with AD demonstrated striking alterations of cellular responsiveness. These changes ranged from enhanced to decreased phagocyte functions, depending on the activity of the infectious disorder. Chemotaxis of PMN and MO was depressed around the third day after onset of the infectious disease. In the beginning of infection, there was a decreased O2- generation and beta-glucuronidase release in PMNs. In MOs, both parameters were enhanced. The results of these investigations provide evidence that functional abnormalities of phagocytes observed in patients with AD are sequelae of concomitant skin infections and not signs of an intrinsic defect present in MOs and PMNs.

Adolescent↗
PubMed1989

A role of Ia-associated invariant chains in antigen processing and presentation.

Most native antigens require processing in a cellular compartment for efficient presentation to T helper cells. The cellular elements that permit processing are not known. We investigated a possible role of the class II MHC-associated invariant chains in antigen processing. Fibroblast cells that were transfected with class II genes were compared with fibroblasts supertransfected with the invariant chain gene for their capacity to present the fifth component of complement (C5) to C5-specific class II restricted T cell clones or influenza virus protein to a virus-specific T cell clone. Only fibroblasts supertransfected with the invariant chain gene were able to present native antigen, even at very low antigen concentration, whereas both fibroblast types could present cyanogen bromide-fragmented C5 or the virus peptide. Presentation of intact antigen but not of fragmented antigen was totally abrogated by treatment of fibroblasts with chloroquine. The invariant chain gene encodes two polypeptides, li31 and li41. Expression of either li31 or li41 was sufficient to render class II-expressing fibroblasts capable of presenting intact antigen.

Animals↗
PubMed1984

Membrane attack by complement.

Membrane attack by complement involves the self-assembly on membranes of five hydrophilic proteins (C5b, C6, C7, C8 and C9) to an amphiphilic tubular complex comprising approximately 20 subunits. The hydrophilic-amphiphilic transition of the precursor proteins is achieved by restricted unfolding and exposure of previously hidden hydrophobic domains. Restricted unfolding, in turn, is driven by high-affinity protein-protein interactions resulting in the formation of amphilic complexes. Circular polymerization of C9 to a tubular complex (poly C9) constitutes the molecular mechanism for transmembrane channel assembly and formation of ultrastructural membrane lesions.

Animals↗
PubMed1986

Role of the N-terminal regions of hog C3a, C5a and C5a-desArg in their biological activities.

The N-terminal regions of the complement peptides C3a, C5a and C5a-desArg (purified from yeast-activated hog serum) were gradually shortened by incubation with leucine amino peptidase. This treatment led to the following changes in the biological activities of these peptides: the potencies of C5a and C5a-desArg in aggregation of human polymorphonuclear leukocytes and of guinea-pig platelets, and their ability to deactivate these cells were gradually diminished; the chemotactic effect of C5a-desArg on human leukocytes was similarly lowered, while the chemotactic potency of C5a was even increased up to the loss of the first 12 N-terminal amino acids. However, after removal of the whole N-terminal region (i.e. 20 amino acids distal of the first disulfide bridge) the potency of both peptides was decreased to a few percent. In contrast, C3a totally lost its platelet-aggregating as well as deactivating activity already after cleavage of 10-15 N-terminal amino acids by LAP. On leukocytes, on the other hand, C3a retained some activity even after the loss of the whole N-terminal region. These results indicate that the N-terminal regions play an important role for biological activities of the three complement peptides, possibly by stabilizing the optimal conformation of their C-terminal regions which contain the receptor-activating domains.

Animals↗
PubMed1982

5,8,11,14-Eicosatetraynoic acid (ETYA) inhibits binding of N-formyl-methionyl-leucyl-phenylalanine (FLMP) to its receptor on human granulocytes. A note of caution.

Binding of two biochemically chemotactic factors, FMLP and C5a, to their respective receptors on human granulocytes produces a transient several-fold increase in cAMP. To determine if arachidonic acid metabolites were responsible for the increased cAMP concentrations, two inhibitors of arachidonic acid metabolism, indomethacin and ETYA, were incubated with granulocytes prior to FMLP or C5A. ETYA, but not indomethacin, inhibited both the cAMP and superoxide responses to a similar degree. However, the mechanism of this effect was found to be through inhibition of the binding of FMLP to its receptor rather than through inhibition of arachidonate metabolism.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1983

Platelet-activating factor-mediated contraction of rabbit lung strips: pharmacologic modulation.

Synthetic platelet-activating factor (PAF) (1-0-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, AGEPC) has been shown to induce a slowly developing contraction of rabbit lung parenchymal strips in an isolated organ bath. The spasmogenic effect of AGEPC appeared to be mediated by specific receptors distinct from H1, H2, cholinergic and C5a anaphylatoxin receptors. Prior exposure to AGEPC induced specific desensitization of lung parenchymal strips. Experiments with several pharmacological agents indicated that AGEPC-induced contraction was independent from cyclooxygenase, but was blocked when phospholipase A2 and lipoxygenase were inhibited and when the Ca++ channels were antagonized. Corticosteroids exhibited an inhibitory effect specific for AGEPC. Intracellular levels of cyclic AMP or cyclic GMP seemed to have a modulatory role in AGEPC-induced contraction of rabbit lung parenchymal strips.

Acetylcholine↗
PubMed1983

Effects of C5a on guinea pig lung: histamine release and mechanism of contraction.

C5a, a product of complement system activation, causes a significant contraction of the isolated guinea pig trachea, and the antihistamine diphenhydramine does not alter the rate, amplitude, or duration of the contraction (Regal et al., 1980). The present study demonstrates that over the range of C5a concentrations investigated, the C5a-induced contractile response of the trachea maximized, whereas the contraction of lung parenchymal strips and the release of histamine from chopped lung did not. In addition, the antihistamines, diphenhydramine and pyrilamine, caused a significant delay in the onset of the C5a-induced contraction of lung parenchymal strips. When parenchymal strips from nonperfused lung were used, the maximum of the contraction was also reduced by pyrilamine. Aspirin and indomethacin effectively inhibited the C5a-induced contraction of lung parenchymal strips, and inhibition by a combination of aspirin and pyrilamine was the sum of the inhibition by aspirin and the inhibition by pyrilamine. The SRS-A antagonist, FPL 55712, caused a more rapid relaxation of the C5a-induced response over control. These studies suggest that products of the cyclo-oxygenase pathway are mediators involved in the C5a-induced contraction of lung parenchyma, with histamine and leukotrienes contributing as well.

Animals↗
PubMed1984

Effects of human anaphylatoxins on guinea pig atria.

Purified human C3a and C5a produce positive inotropic effects on spontaneously contracting atria isolated from guinea pigs. The increased amplitude of contraction induced by C5a has a threshold at 1 X 10(-9)M. This effect is concentration dependent, increasing by 180% at 1.7 X 10(-7)M C5a. The threshold concentration for a C3a-induced effect is four times greater than that for C5a. The C3a-induced effect is also concentration dependent, maximizing at 1 X 10(-7)M. Above that concentration, the increased response to C3a reaches a plateau value at approximately a 70% greater amplitude than that of untreated tissue. Unlike effects induced by anaphylatoxins in other tissues, these positive inotropic responses are not tachyphylactic. The same atrium will respond repeatedly to either C3a or C5a for a period of up to 4 h. Studies with histamine, leukotriene and prostaglandin inhibitors revealed that the anaphylatoxin-induced responses are not solely histamine mediated. Cimetidine partially inhibited the response of isolated guinea pig atria to C5a (e.g. 25%) and failed to affect the response of this tissue preparation induced by C3a. FPL 55712 inhibited the response to both anaphylatoxins by approximately 40%. The atrial response to C3a was inhibited by more than 70% by indomethacin, whereas the response to C5a was unaffected. This is the first report characterizing the specific action of purified C3a and C5a on isolated cardiac tissue. It was concluded that C3a acts primarily via prostaglandins and leukotrienes while C5a affects contractile intensity via vasoamines and leukotrienes.

Alprostadil↗
PubMed1986

Anaphylatoxin C5a fails to promote prostacyclin release in cultured endothelial cells from human umbilical veins.

Subcultured endothelial cells from human umbilical veins respond to histamine and melittin with increased prostacyclin production, measured as 6-keto-prostaglandin F1 alpha by radioimmunoassay. However, no response to leukotriene C4 was observed. Primary cultured cells, on the other hand, respond to leukotriene C4 and the histamine response was 7 times more potent for these cells than for subcultured cells. In contrast, neither primary cultures nor subcultures of endothelial cells released prostacyclin following application of either human anaphylatoxin C5a (100 nM) or C3a (1 microM). In addition, these endothelial cells appear to have no specific binding sites for 125I-C5a. However, endothelial cells released prostacyclin in the presence of human polymorphonuclear leukocytes that were activated with C5a. We conclude that involvement of endothelial cells in the haemodynamic response to anaphylatoxin is an indirect function, i.e. C5a activates circulating or tissue cells which in turn stimulate the endothelial cell to produce prostacyclin.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Bioactive complement fragments in immunoregulation.

Several fragments derived from complement components have been identified as potent effector substances in in vitro assays that measure cell proliferation and antibody synthesis. The anaphylatoxin C3a suppresses the immune response but fails to influence T- or B-cell proliferation. The factor C5a augments both antibody production and antigen-induced, but not mitogen-induced, T-cell proliferation. C3a-mediated suppression occurs through the activation of a suppressor T-cell cascade with macrophage collaboration. C5a-mediated enhancement, depending upon the in vitro system studied, acts at the level of the helper T cell and/or macrophage. A fragment generated from treating iC3b with kallikrein (c3d-K) has aided in defining a structural region of the C3b molecule that can influence the level of circulating leukocytes. The factor C3d-K is also capable of suppressing both specific and non-specific T-cell proliferative responses and mitogen-induced B cell growth. The mechanism of C3d-K action is defined as a direct effect on "activated" T cells, even though IL-2 synthesis of treated cells is diminished. The effect of C3d-K is long lasting, non-reversible and requires only a short exposure to the target cell.

Animals↗
PubMed1986

Eosinophil-mediated cellular cytotoxicity induced by zymosan-activated serum.

The aim of the present work was to develop an in vitro model of eosinophil cytotoxicity which mimics numerous in vivo situations characterized by complement activation through the alternative pathway. Our results demonstrate that eosinophilic granulocytes from patients with parasitic diseases and blood eosinophilia were able to damage chicken red blood cells when incubated with zymosan-activated serum (ZAS) as assessed by a 51Cr release assay. The phenomenon was independent of the presence of antibodies directed against the target cells and related to the quantity of ZAS added to the wells. As target cell lysis is totally or partially inhibited by catalase, sodium azide and potassium cyanide, an involvement of toxic oxygen derivatives as cytolytic mediators was suggested.

Azides↗
PubMed1987

Psychopharmacological activity of immune complexes in rat brain is complement dependent.

Sprague-Dawley male rats implanted with chronic indwelling cannulae at the perifornical hypothalamus eat excessively during the sixth hour following administration of exogenous immune-complexing reactants to the brain site. Rabbit anti-HSA was injected, followed in 30 min by a 20-fold excess of antigen. Anaphylatoxin C5a has also been shown to induce excessive intake, an effect similar to that of norepinephrine at this brain site. If the anaphylatoxins or other byproducts or consequence of the complement cascade were responsible for the immune complex effect, interference with the initiation of the cascade or with the conversion of C3 to C3a and C3b should abolish the behavioral response. These experiments demonstrate that immune complexes formed with the non-complement-fixing F(ab')2 fragment of the rabbit anti-HSA do not induce eating, and that normally active IgG antibody complexes do not induce eating if the site has been pretreated with goat anti-rat C3. This latter treatment had no effect, however, on the ability of the animals to respond to norepinephrine or to C5a. We conclude that the immune complex effect is complement dependent.

Animals↗
PubMed1983

Intracellular or extracellular calcium can be used to trigger C5a-stimulated enzyme secretion from rabbit neutrophils.

The ability of C5a to stimulate lysosomal enzyme release and 45Ca2+ efflux from rabbit neutrophils was studied. C5a stimulated beta-glucuronidase release from cytochalasin B-treated neutrophils either in the presence or absence of extracellular calcium. Depletion of cell calcium by pretreatment with the calcium ionophore A23187 blocked both the ability of C5a to elicit enzyme release in the absence of extracellular calcium and its ability to stimulate 45Ca2+ efflux. Both actions were dose-dependent over the same concentration range (10(-8)-10(-6) M ionophore A23187). In contrast, ionophore pretreatment had no effect on C5a-stimulated enzyme release in the presence of extracellular calcium. These results suggest that (a) release of cell calcium is required for enzyme secretion in the absence of extracellular calcium, and (b) C5a can trigger near-maximal enzyme release by using calcium from either of two sources: the extracellular space or an intracellular site.

Animals↗
PubMed1983

C5a and antigen-induced tracheal contraction: effect of a combination of an antihistamine and cyclo-oxygenase inhibitors.

Our previous studies with C5a, a cleavage product of the fifth component of complement, have shown that the antihistamine diphenhydramine and the cyclo-oxygenase inhibitor aspirin do not inhibit the C5a-induced contraction of isolated guinea pig trachea (Regal, Eastman & Pickering, 1980; Regal & Pickering, 1981). We investigated the effect of cyclo-oxygenase inhibitors in the presence of diphenhydramine to determine if cyclo-oxygenase products were contributing to the contraction beyond any effect they might have on histamine release. A combination of a cyclo-oxygenase inhibitor and diphenhydramine caused a delay in onset and decrease in magnitude and duration of the C5a-induced contraction. Indomethacin itself also caused a slight inhibition. In contrast, a combination of aspirin and diphenhydramine did not inhibit the initial portion of antigen-induced tracheal contraction any more than diphenhydramine alone and enhanced the later portion just as aspirin alone. Cross tachyphylaxis experiments demonstrated that antigen pretreatment significantly inhibited a subsequent C5a-induced tracheal contraction, though C5a pretreatment did not affect a subsequent antigen-induced contraction. Thus, cyclo-oxygenase products do contribute to C5a-induced tracheal contraction, and histamine participation in the presence of cyclo-oxygenase inhibitors is suggested. Our studies demonstrate the dissimilarities of C5a and antigen-induced contraction as regards inhibition by aspirin plus diphenhydramine, yet suggest common pathways leading to the contractile response as evidenced by cross tachyphylaxis experiments.

Animals↗
PubMed1987

Influence of lysophospholipids and PAF on the oxidative burst of PMNL.

Lysophosphatidylcholine (LC), platelet activating factor (PAF) and its precursor lysophosphatidalcholine (LP) enhance O-2-release by polymorphonuclear leucocytes (PMNL) triggered by PMA whereas lysophospholipids with other polar headgroups fail to do so. The generation of these lysophosphatidylcholine-like molecules appears to represent an essential step in the activation of the oxidative burst of the PMNL triggered by PMA since inhibition of phospholipase A2 (PLA2) by p-bromophenacylbromide (BB) or mepacrine results in an inhibition of the O-2 release. This inhibition seems to be due to the reduced generation of the phospholipids studied as it could be reversed by LP. In addition, stimulation of the oxidative burst of the PMNL by the chemotactic stimuli, N-formyl-methionyl-leucylphenylalanine (FMLP), and the complement fragment C5a could also be significantly enhanced by LP as shown by chemiluminescence. However, the response to the phagocytic stimulus, opsonized zymosan (Zx), is not affected by LP. These data provide evidence for the participation of phospholipid metabolism in the initiation of the oxidative burst of PMNL induced by the soluble monomeric stimuli PMA, FMLP and C5a.

Acetophenones↗