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Biomedical subjects

N Haeffner-Cavaillon

Publications and source records attributed to N Haeffner-Cavaillon.

At least 73 records · Page 4Linked to original sources
PubMed1990

Induction of IL-1 during hemodialysis: transmembrane passage of intact endotoxins (LPS).

Circulating monocytes of patients undergoing chronic hemodialysis are triggered to produce interleukin-1 (IL-1) in vivo. Intradialytic induction of IL-1 is associated with complement activation in patients dialyzed with first-use cellulose membranes. Chronic stimulation of IL-1 production occurs because of an yet unidentified mechanism in patients dialyzed with high permeability membranes. The present study demonstrates that intact bacterial lipopolysaccharide (LPS) molecules may cross cuprophan, AN69 and polysulfone membranes under in vitro conditions simulating in vivo hemodialysis. The experiments used purified LPS from Neisseria meningitidis and LPS from Pseudomonas testosteroni, a bacterial strain grown out from a clinically used dialysate. LPS were purified to homogeneity and radiolabeled. Transmembrane passage of 3H-labeled LPS was observed within the first five minutes of dialysis. A total of 0.1 to 1% of 3H-labeled LPS were recovered in the dialysate compartment after one hour of dialysis. High amounts of LPS, representing 40 to 70% of the amount originally present in the dialysate, were absorbed onto high permeability membranes. Low amounts of LPS were absorbed onto cuprophan membranes. The amount of LPS absorbed decreased with the concentration of LPS in the dialysate. LPS recovered from the blood compartment exhibited the same molecular weight as that used to contaminate the dialysate. Biochemically detectable transmembrane passage of LPS was not associated with that of material detectable using the limulus amebocyte lysate (LAL) assay. An IL-1-inducing activity was, however, detected in the blood compartment upon dialysis with high permeability membranes, as previously found by others with cuprophan membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylic Resins↗
PubMed1990

Zidovudine inhibits functional extracellular monocytic interleukin-1.

Zidovudine (AZT) penetrates human monocytes to exert its antiretroviral activity at the level of reverse transcriptase in infected cells. Stimulation of normal human monocytes with lipopolysaccharide (LPS) results in the transcription of interleukin-1 (IL-1) genes, the intracellular accumulation of IL-1 alpha and IL-1 beta precursors, and the subsequent extracellular release of functional IL-1 beta. The present study demonstrates that zidovudine inhibits the extracellular release of IL-1 activity without affecting the generation of intracellular IL-1 or the amount of released IL-1 beta protein. Similar results were observed with monocytes from normal individuals and monocytes from patients with AIDS. Since IL-1 may upregulate the expression of HIV genes in infected cells, the inhibitory effect of zidovudine on the release of functional IL-1 may be relevant for the beneficial effect of the drug in HIV infection.

Extracellular Space↗
PubMed1990

Cytokine response by monocytes and macrophages to free and lipoprotein-bound lipopolysaccharide.

Recent evidence suggests that bacterial lipopolysaccharide binds to serum lipoproteins in vitro and in vivo and that lipopolysaccharide in the form that is bound to lipoprotein is less biologically active in several experimental models. In order to study the mechanism of this apparent detoxification, we compared the ability of free and lipoprotein-bound lipopolysaccharide from Escherichia coli O18 to stimulate interleukin-1, interleukin-6, and tumor necrosis factor from elicited murine peritoneal macrophages and circulating human monocytes. Lipopolysaccharide bound to lipoprotein was 20- to 1,000-fold less active than the unbound form in inducing the release of each cytokine. We also studied the binding of each form of lipopolysaccharide to the macrophage surface. Lipopolysaccharide complexed to lipoprotein was unable to compete for the binding of radiolabeled heterologous lipopolysaccharide to murine macrophages, and radiolabeled lipopolysaccharide-lipoprotein complexes bound poorly compared with molar equivalents of free lipopolysaccharide. Our experiments suggest that in the process of binding to lipoproteins, lipopolysaccharide may be rendered less toxic through a mechanism of decreased ability to induce monocytes and macrophages to release cytokines, perhaps because of an altered interaction at the cell surface.

Animals↗
PubMed1989

Human T cells and interleukin 4 inhibit the release of interleukin 1 induced by lipopolysaccharide in serum-free cultures of autologous monocytes.

Stimulation with lipopolysaccharide (LPS) of unfractionated peripheral blood mononuclear cells in serum-free cultures resulted in the release of lower amounts of interleukin (IL) 1 as compared with those induced in cultures of purified monocytes. In addition, a dose-dependent decrease in IL 1 production was observed when purified autologous T cells were added to cultures of LPS-stimulated monocytes. The inhibitory effect of T cells on IL 1 production was reproduced by adding human recombinant IL 4 to monocyte cultures. IL 4 optimally inhibited the generation of cell-associated IL 1 and the extracellular release of IL 1 in monocyte cultures performed in the presence of low doses of LPS. IL 4 inhibited the generation of IL 1 activity and that of IL 1 alpha and IL 1 beta antigens indicating that IL 4 interfered with IL 1 transcription and/or processing rather than induced the synthesis of an IL 1 inhibitor. IL 2 and IL 3 enhanced IL 1 production by LPS-stimulated cells whereas granulocyte-monocyte colony-stimulating factor had no effect. IL 4 inhibited the production and the release of tumor necrosis factor alpha activity by monocytes stimulated with LPS. Thus, T cells and IL 4 may down-regulate the production of monokines which induce their proliferation and exert a suppressive effect on the generation of potent proinflammatory mediators.

Cells, Cultured↗
PubMed1989

Interleukin-1 induction by lipopolysaccharides: structural requirements of the 3-deoxy-D-manno-2-octulosonic acid (KDO).

We previously showed the importance of the 3-deoxy-D-manno-2-octulosonic acid (KDO) residue in endotoxins (lipopolysaccharides, LPS) for the induction of the synthesis and release of interleukin-1 (IL-1) by human monocytes. We further investigated the effect of some structural variations within the KDO molecule on IL-1 production induced by LPS. Deamination of Bordetella pertussis LPS, followed by mild anhydrous acidic methanolysis released a hexasaccharide (fragment B'), which had a terminal methyl ketoside KDO residue with a methyl-esterified carboxyl group. This fragment was unable to induce IL-1 production by human monocytes. Fragment B' could be converted into an active hexasaccharide by de-esterification (fragment B-OMe), but not by reduction of the methyl ester group. The KDO residues in the LPS of some bacterial species have been shown to be phosphorylated and we observed that these LPS were weak IL-1 inducers. Phosphorylated KDO present in Vibrio cholerae and B. pertussis LPS respond poorly in the thiobarbiturate assay (specific for KDO). However, if these LPS were dephosphorylated with aqueous hydrofluoric acid (HF) their KDO response in this assay was increased 5.4- to 2.6-fold, respectively. In parallel, the HF-treated LPS were more potent IL-1 inducers than untreated endotoxins. These data confirm that the KDO residue(s) present in all endotoxins play(s) a major role in the signal(s) leading to IL-1 production by human monocytes, and show that IL-1 induction by LPS (1) requires a free carboxyl group in the KDO and (2) is correlated with the degree of substitution of the KDO.

Animals↗
PubMed1989

In vivo induction of interleukin-1 during hemodialysis.

In vivo induction of interleukin-1 (IL-1) production during hemodialysis was investigated by measuring IL-1 activity in monocyte lysates from 59 patients undergoing long-term maintenance hemodialysis with complement activating and non-complement activating devices. In patients dialyzed with new hollow-fiber cuprophane dialyzers, predialytic (T0) monocyte-associated IL-1 activity was 12.5 +/- 3.0 U/ml (mean +/- SEM), a value that was higher than that found in normal individuals (2.85 +/- 0.85 U/ml; P less than 0.0025) and in non-dialyzed patients with chronic renal failure (0.95 +/- 0.85 U/ml, P less than 0.0001). Cell-associated IL-1 activity was consistently increased after five hours of dialysis with cuprophane membranes (42.4 +/- 5.5 U/ml, P less than 0.0005). Systemic complement activation was demonstrated by the finding of increased plasma levels of C3adesArg antigen during dialysis. In patients dialyzed with high permeability polyacrylonitrile and polysulfone membranes, no intradialytic change in cell-associated IL-1 and no complement activation occurred. However, the mean predialytic values of monocyte-associated IL-1 in these patients (that is, 32.9 +/- 5.6 U/ml and 38 +/- 5.65 U/ml for the polyacrylonitrile and the polysulfone groups, respectively) were higher than the predialytic levels of cell-associated IL-1 in the patients from the cuprophane group (P less than 0.0025). Monocytes obtained at the beginning and five hours of dialysis from patients dialyzed with polyacrylonitrile devices, and monocytes obtained at five hours but not at the beginning of dialysis from patients dialyzed with cuprophane membranes, spontaneously released extracellular IL-1 after 24 hours of culture in serum free conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

HIV infection is associated with the spontaneous production of interleukin-1 (IL-1) in vivo and with an abnormal release of IL-1 alpha in vitro.

Interleukin-1 (IL-1) is not constitutively produced by normal human monocytes. We have investigated the production of cell-associated IL-1 in uncultured unstimulated adherent monocytes from HIV-infected patients, which reflects ongoing generation of IL-1 by the cells in vivo. High levels of cell-associated IL-1 activity and of cell-associated IL-1 alpha and IL-1 beta antigens were found in monocytes from HIV-infected patients as compared with those found in monocytes from normal individuals. Amounts of cell-associated IL-1 were high in patients with AIDS and in patients from Centers for Disease Control groups II and III. Serum-free culture for 24 h of monocytes from HIV-infected individuals in the absence of lipopolysaccharides (LPS) resulted in spontaneous release of IL-1 activity from the cells whereas no release occurred upon culture of normal cells. Stimulation of monocytes with LPS induced the release of IL-1 alpha and IL-1 beta from cells of infected patients. Only IL-1 beta was released from cells of normal individuals. Thus, circulating monocytes from HIV-infected patients are triggered to produce IL-1 in vivo. The present study also indicates that HIV infection is associated with an acquired defect in the intracellular processes regulating IL-1 secretion.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Dissociation of cell-associated interleukin-1 (IL-1) and IL-1 release induced by lipopolysaccharide and lipid A.

The capacities of lipopolysaccharide (LPS) and lipid A to trigger mouse BALB/c peritoneal macrophages and to induce the production of cell-associated interleukin-1 (IL-1) and membrane-associated IL-1 and IL-1 release have been compared. Bordetella pertussis lipid A was 1,000 to 10,000 times less efficient than the native LPS to induce IL-1 release by freshly isolated elicited macrophages. When resident macrophages were studied, lipid A, at high concentrations (greater than 2 micrograms/ml), induced significant levels of cell-associated IL-1 but little or no IL-1 release. With synthetic lipid A built up with the Escherichia coli lipid A structure (compound 506), IL-1 activity was present in the supernatants of elicited peritoneal macrophages and to a lesser extent in those of resident macrophages. However, the release of IL-1 induced by synthetic lipid A 506 remained much lower than those induced by rough LPS. Membrane-associated IL-1 could be induced on BALB/c macrophages with LPS and natural or synthetic lipid A, the LPS being the most active. In C3H/HeJ mice, neither natural nor synthetic lipid A could induce detectable cell-associated IL-1, whereas LPS could induce cell-associated and membrane IL-1 activity but no IL-1 release. Our results indicate that fragments of endotoxins may induce the production of IL-1 but the entire structure of the LPS molecule is the most effective to induce intracellular IL-1 production, expression of membrane IL-1, and release of IL-1.

Animals↗
PubMed1989

The human C3b receptor (CR1).

The human complement system is comprised of 19 plasma components and regulatory proteins and of at least 9 distinct cellular receptors for these proteins or their activation fragments. The important role of complement in host defense against infection is related to its capacity to opsonize microorganisms, lyze target cells, and induce the release of inflammatory mediators from leukocytes. Complement participates in the processing and clearance of immune complexes and in regulation of the immune response. Most of the biologic effects derived from complement activation depend on ligand-receptor interactions between complement proteins or their cleavage fragments and specific receptors on cells. Two types of ligands are generated during complement activation: soluble low-molecular-weight ligands, such as the anaphylatoxins C3a and C5a, and so-called bifunctional ligands that attach both to the target of complement activation (opsonins) and to the appropriate receptor on effector cells. The most abundant complement protein in plasma is C3. Activation of the classic and alternative complement pathways generates C3 convertases that cleave C3 into an anaphylatoxic fragment, C3a, and a major fragment, C3b, which is capable of forming a covalent linkage with the targets of complement activation. Surface-bound C3b is the preferential ligand for the C3b receptor, CR1 (CD 35), which is expressed on most peripheral blood cells. The receptor plays an important role in the processing of immune complexes, the phagocytosis of C3b-bearing microorganisms, and regulation of the immune response. The cellular expression of the molecule is decreased in patients with systemic lupus erythematosus (SLE) and in patients infected with the human immunodeficiency virus (HIV).

Antigen-Antibody Complex↗
PubMed1989

Induction of interleukin-1 production in patients undergoing cardiopulmonary bypass.

Systemic reactions resembling inflammation occur in patients undergoing cardiopulmonary bypass. We now report that interleukin-1, an endogenous pyrogen and a key mediator of inflammation, is transiently and consistently generated in vivo by circulating monocytes within hours after cardiopulmonary bypass. Interleukin-1 production was assessed by measuring interleukin-1 functional activity and interleukin-1 beta antigen concentration in cell lysates from monocytes of patients during and after bypass. There was no increase in intracellular interleukin-1 activity during bypass and within the first hours after bypass, possibly because of a suppressive effect of hypothermia on interleukin-1 production, as documented in vitro. Maximal generation of interleukin-1 was observed 24 hours after extracorporeal circulation, concomitantly with the occurrence of a peak in body temperature. The amount of interleukin-1 generated at that time was linearly correlated with the increase in patients' body temperature. The peak in interleukin-1 production followed by 20 hours the peak in complement activation as assessed by determining C3a desArg and C5a desArg concentrations in patients' plasma. These results indicate that interleukin-1 may be involved in the pathogenesis of adverse systemic reactions associated with cardiopulmonary bypass.

Adult↗
PubMed1987

C3a(C3adesArg) induces production and release of interleukin 1 by cultured human monocytes.

Purified human C3a(C3adesArg) induced dose-dependent generation of intracellular IL 1 activity and release of IL 1 in cultures of human mononuclear adherent cells in serum-free conditions. Concentrations of C3a(C3adesArg) of 10(-8) M and 6 hr of culture were sufficient to induce production of cell-associated IL 1, as detected in monocyte lysates. Ten- to 100-fold higher concentrations of C3a(C3adesArg) and 24 hr of culture were required for induction of IL 1 release. Release of IL 1 induced by suboptimal amounts of C3a(C3adesArg) was greatly enhanced by the addition of indomethacin to the culture medium. Contamination with C5a of the C3a(C3adesArg) preparation did not account for C3a(C3adesArg)-induced IL 1 production. Induction of IL 1 activity by C3a(C3adesArg) was not due to contaminating LPS, as indicated by the following observations: the amount of contaminating LPS in C3a(C3adesArg) was below that which could induce IL 1 release from human monocytes in serum-free conditions; induction of IL 1 by C3a(C3adesArg) was not suppressed by polymyxin B; kinetics of IL 1 production and release in the presence of C3a(C3adesArg) differed from those observed in the presence of LPS; and sialated gangliosides, which inhibit IL 1 release induced by LPS, had no effect on the induction of IL 1 by C3a(C3adesArg). The C3a(C3adesArg) preparation used in this study mostly contained the desArg derivative, suggesting that, in contrast with the requirement for an intact C-terminal arginyl residue for the spasmogenic activity of C3a, both C3a and its C3adesArg derivative may interact with receptors on human monocytes. By inducing IL 1 production and release, C3a(C3adesArg) may contribute to the generation of the inflammatory process and the regulation of the immune response.

Cells, Cultured↗
PubMed1987

Inhibition by gangliosides of the specific binding of lipopolysaccharide (LPS) to human monocytes prevents LPS-induced interleukin-1 production.

In a previous work we have reported that gangliosides inhibit interleukin 1 (IL-1) release by human monocytes stimulated with lipopolysaccharides (LPS). In the present study we extend this work to IL-1 production and we correlate these observations with the capacity of gangliosides to inhibit the binding of radiolabeled LPS to its specific receptor on human monocytes. Preincubation of 3H-LPS with crude bovine brain gangliosides, as well as purified human brain mono, di, and trisialogangliosides (GM1, GD1a, and GT1b, respectively), led to an inhibition of the specific binding of LPS to the cell surface. Neither ceramide nor N-acetyl neuraminic acid, two constituents of gangliosides, was able by itself to inhibit the specific binding. A strict parallelism was observed with respect to inhibition on LPS-induced IL-1 production and release. Asialoganglioside (asialo-GM1) was inactive in both assays, suggesting that the N-acetyl neuraminic acid plays a role within the ganglioside molecule, with respect to inhibitory activity. We conclude that LPS-induced production and release by human monocytes is not due to a signal triggered by nonspecific absorption and/or intercalation of LPS into cell membrane which occur through hydrophobic interaction mediated by the lipid A region. Addition of exogenous sialogangliosides which blocked LPS-induced IL-1 production and release, did not modify significantly the nonspecific binding of 3H-LPS, whereas it did inhibit the specific binding which is mediated by the polysaccharide moiety of the LPS molecule. These results establish a relationship between the specific endotoxin receptor on monocytes and a LPS-induced cellular function.

Binding, Competitive↗
PubMed1986

Molecular requirement for interleukin 1 induction by lipopolysaccharide-stimulated human monocytes: involvement of the heptosyl-2-keto-3-deoxyoctulosonate region.

Experiments were undertaken to localize in the lipopolysaccharide (LPS) the minimal structural determinants sufficient to initiate the signal leading to interleukin 1 (IL 1) secretion by human monocytes. Our results clearly demonstrated that this signal is triggered by structures present in the so-called inner-core region which chemically consists of 2-keto-3-deoxy-D-manno-octulosonic acid (KDO) and heptose in many LPS of gram-negative bacteria. Thus, the isolated polysaccharide region of Bordetella pertussis endotoxin as well as fragments derived therefrom containing the reducing KDO unit were able to induce similar levels of IL1 induction as the native LPS. Similarly, the trisaccharide alpha-D-manno-heptopyranosyl-(1-3)-alpha-D-manno-heptopyranosyl -(1-5)-3 -deoxy-D-manno-octulosonic acid (hep-hep-KDO), representative for the inner-core region of a large number of enterobacterial LPS, was a very potent IL 1 inducer. Neither KDO monosaccharide, nor the alpha-(2-4)-linked 3-deoxy-D-manno-octulosonic acid disaccharide isolated from Salmonella rough-form LPS promoted the signal indicating that the minimal structure of endotoxin able to induce IL 1 secretion resides in the hep (1-5)-KDO disaccharide.

Carbohydrate Sequence↗