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Biomedical subjects

J L Bodmer

Publications and source records attributed to J L Bodmer.

33 records · Page 2Linked to original sources
PubMed1997

Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors.

Viruses have evolved many distinct strategies to avoid the host's apoptotic response. Here we describe a new family of viral inhibitors (v-FLIPs) which interfere with apoptosis signalled through death receptors and which are present in several gamma-herpesviruses (including Kaposi's-sarcoma-associated human herpesvirus-8), as well as in the tumorigenic human molluscipoxvirus. v-FLIPs contain two death-effector domains which interact with the adaptor protein FADD, and this inhibits the recruitment and activation of the protease FLICE by the CD95 death receptor. Cells expressing v-FLIPs are protected against apoptosis induced by CD95 or by the related death receptors TRAMP and TRAIL-R. The herpesvirus saimiri FLIP is detected late during the lytic viral replication cycle, at a time when host cells are partially protected from CD95-ligand-mediated apoptosis. Protection of virus-infected cells against death-receptor-induced apoptosis may lead to higher virus production and contribute to the persistence and oncogenicity of several FLIP-encoding viruses.

Adaptor Proteins, Signal Transducing↗
PubMed1997

TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95).

A novel member of the tumor necrosis factor (TNF) receptor family, designated TRAMP, has been identified. The structural organization of the 393 amino acid long human TRAMP is most homologous to TNF receptor 1. TRAMP is abundantly expressed on thymocytes and lymphocytes. Its extracellular domain is composed of four cysteine-rich domains, and the cytoplasmic region contains a death domain known to signal apoptosis. Overexpression of TRAMP leads to two major responses, NF-kappaB activation and apoptosis. TRAMP-induced cell death is inhibited by an inhibitor of ICE-like proteases, but not by Bcl-2. In addition, TRAMP does not appear to interact with any of the known apoptosis-inducing ligands of the TNF family.

Adaptor Proteins, Signal Transducing↗
PubMed1997

TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB.

TRAIL induces apoptosis through two closely related receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Here we show that TRAIL-R1 can associate with TRAIL-R2, suggesting that TRAIL may signal through heteroreceptor signaling complexes. Both TRAIL receptors bind the adaptor molecules FADD and TRADD, and both death signals are interrupted by a dominant negative form of FADD and by the FLICE-inhibitory protein FLIP. The recruitment of TRADD may explain the potent activation of NF-kappaB observed by TRAIL receptors. Thus, TRAIL receptors can signal both death and gene transcription, functions reminiscent of those of TNFR1 and TRAMP, two other members of the death receptor family.

Adaptor Proteins, Signal Transducing↗
PubMed1990

Experimental osteoarthritis in guinea-pigs.

Cartilage degeneration was induced in the hind knees of guinea-pigs by surgery. Partial medial meniscectomy induced rapidly progressing lesions whereas the lesions induced by section of the lateral collateral ligament with or without section of the medial collateral ligament developed later and progressed more slowly. In all cases the lesions were first seen focally on the medial tibial plateau where they extended both laterally and deeper into the cartilage. Later, lesions appeared on the medial femoral condyle and meniscus, and eventually also on cartilage in the lateral joint compartment. During the later stages, these models had many features of human osteoarthritis. The appearance and progression of spontaneous lesions in the hyaline cartilage of the hind knees of young guinea-pigs first reported by Bendele and Hulman (1988) has been confirmed. Extra ascorbic acid added to the drinking water had a slight chondroprotective effect on the development of spontaneous lesions but gave no significant protection against the development of lesions induced by lateral collateral ligament section.

Animals↗
PubMed1987

Stimulated release of neutral proteinases elastase and cathepsin G from inflammatory rat polymorphonuclear leukocytes.

Rat leukocytes from inflammatory peritoneal exudates respond in vitro to a variety of chemotactic and phagocytic stimuli by releasing both elastase and cathepsin G neutral proteinase enzyme activities. PAF, FMLP, and PMA stimulated a rapid, cytochalasin B-dependent, dose-related release of both enzymes; however, leukotriene B4 was inactive. It was not possible to measure the activity of zymosan-activated serum on these cells as rat serum contains high levels of proteinase inhibitors. The calcium ionophore A23187 stimulated a dose-related, time-dependent, cytochalasin B-independent enzyme release. Concanavalin A stimulated a weak, nondose-related release of enzyme activity. Zymosan and serum-coated zymosan stimulated enzyme secretion which was markedly inhibited by the presence of cytochalasin B. These data indicate that release of azurophillic granule neutral proteinases from rat inflammatory leukocytes can be detected and quantitated in vitro. This model could provide a test system for monitoring the pattern and specificity of enzyme release from azurophil granules. The ability of a variety of stimuli to induce proteolytic enzyme release from inflammatory neutrophils may be of considerable relevance to chronic inflammatory diseases.

Animals↗
PubMed1987

Kinetic studies on the interaction of eglin c with human leukocyte elastase and cathepsin G.

We have investigated the inhibition of human leukocyte elastase and cathepsin G by recombinant Eglin c under near physiological conditions. The association rate constants k on of Eglin c for elastase and cathepsin G were 1.3 X 10(7) M-1 s-1 and 2 X 10(6) M-1 s-1, respectively. Under identical conditions, the k on for the association of human plasma alpha 1-proteinase inhibitor with the two leukocproteinases were 2.4 X 10(7) M-1 s-1 and 10(6) M-1 s-1, respectively. The consistency of these data could be verified using a set of competition experiments. The elastase-Eglin c interaction was studied in greater detail. The dissociation rate constant k off was determined by trapping of free elastase from an equilibrium mixture of elastase and Eglin c with alpha 1-proteinase inhibitor or alpha 2-macroglobulin. The rate of dissociation was very low (k off = 3.5 X 10(-5) s-1). The calculated equilibrium dissociation constant of the complex, Ki(calc) = k off/k on, was found to be 2.7 X 10(-12) M. Ki was also measured by adding elastase to mixtures of Eglin c and substrate and determining the steady-state rates of substrate hydrolysis. The Ki determined from these experiments (7.5 X 10(-11) M) was significantly higher than Ki(calc). This discrepancy might be explained by assuming that the interaction of Eglin c with elastase involves two steps: a fast binding reaction followed by a slow isomerization step. From the above kinetic constants it may be inferred that at a therapeutic concentration of 5 X 10(-7) M, Eglin c will inhibit leukocyte elastase in one second and will bind this enzyme in a "pseudo-irreversible" manner.

Cathepsin G↗
PubMed1985

Eglin c, a pharmacologically active elastase inhibitor.

Eglin c is an elastase/cathepsin G inhibitor from leech Hirudo medicinalis. The gene for this 70 aminoacid peptide was synthesized chemically, cloned and expressed by E. coli. Here we report biochemical and pharmacological studies. The rate of complex formation between Eglin c and human leukocyte elastase (HLE) or human cathepsin G (H. Cat. G) was determined and compared to those of a number of other proteinase/proteinase-inhibitor interactions (alpha 1 PI and alpha 2M). The association rate constants of Eglin c with the leukocyte enzymes are of the same order of magnitude as those with the naturally occurring inhibitors alpha 1 PI and alpha 2M. The association rate constant of Eglin c (extracted from leech) and Eglin c (biotechnology product) with HLE was found to be identical. The equilibrium constants Ki of the Eglin c/HLE and the Eglin c/H. Cat. G interactions are in the order of 10(-10) M. In an experiment with the hamster emphysema model, 0.5 mg or 2 mg of Eglin c applied intratracheally one hour before an HLE-insult completely protected the animals against emphysema and no signs of toxicity due to Eglin c were observed.

Animals↗
PubMed1984

Plasma proteinase inhibitors.

Plasma proteinase inhibitors account for about 10% of the total protein in plasma. They provide one mechanism for the control of proteinase activity, thus regulating many important biological reactions such as blood coagulation. Most plasma inhibitors are specific for one or a few related proteinases and control a particular biological event or pathway. Two other inhibitors, the alpha 2-macroglobulin (alpha 2M) and the alpha 1-proteinase (alpha 1PI = alpha 1-antitrypsin) have a broader specificity. The role of alpha 1PI, although theoretically able to inhibit a large number of enzymes, is the inhibition of leukocytic elastase. This function is particularly important in the lung where elastase may be released from neutrophils particularly in smokers. alpha 2-Macroglobulin reacts with a large number of very different proteinases by a mechanism quite different from those of the other inhibitors. The physiological role of this inhibitor is not clearly understood although it may act as a "back-up" inhibitor when levels of other inhibitors are low or if no specific inhibitor is available.

Antithrombin III↗
PubMed1983

Does the induction of macrophage lysosomal enzyme secretion by zymosan involve the mannose receptor?

Secretion of the lysosomal enzyme hexosaminidase induced by zymosan is inhibited by mannose and by high concentrations of mannose-6-phosphate and 2-deoxy-glucose but not by mannan. Secretion of hexosaminidase from cells storing previously endocytosed zymosan is unaffected by mannose. Exposure of the cells to mannose does not affect secretion caused by subsequent exposure to zymosan. These findings suggest a role for the mannose-glycoprotein receptor in initiation of lysosomal enzyme secretion by zymosan.

Animals↗
PubMed1983

Receptor-mediated phagocytosis of zymosan is unaffected by some conditions which reduce macrophage lysosomal enzyme secretion.

We have previously shown that several agents which interfere with binding of ligands to the mannose-glycoprotein receptor on macrophages can inhibit zymosan-induced lysosomal enzyme secretion. Here we show that mannose only reduces the association of zymosan with macrophages during the first hour of exposure; after longer periods of uptake no effect is detectable. We have previously shown that mannose reduces surface binding of zymosan, probably by interfering selectively with binding to the mannose receptor. The present inhibition of association of zymosan with macrophages during short exposures can be entirely explained by this reduction of binding. Macrophages must therefore internalize zymosan at sites in addition to the mannose receptor. In contrast to macrophages the murine macrophage-like cell line P388D1 is lacking the mannose-glycoprotein receptor. Accordingly we find that binding of zymosan to P388D1 is much slighter than to macrophages and is unaffected by mannose or mannose-6-phosphate. The spontaneous lysosomal enzyme secretion of P388D1 is also unaffected by mannose. The data on macrophages confirm our previous suggestion that agents interfering with the mannose receptor inhibit the induction of lysosomal enzyme secretion by acting directly on the receptor. The data on P388D1 cells support this assertion by excluding effects at later steps in the secretory pathway.

Animals↗
PubMed1982

The effect of weak bases on lysosomal enzyme secretion by mononuclear phagocytes.

NH4Cl induces a dose-dependent secretion of lysosomal enzymes by mouse peritoneal macrophages and human peripheral blood monocytes. The mechanism of NH4Cl-stimulated hexosaminidase release is distinct from that initiated by the inflammatory stimulus, zymosan. The spontaneous lysosomal secretion of the continuous murine macrophage-like cell line, P388D1, is inhibited by up to 50% in the presence of NH4Cl and other weak bases.

Ammonium Chloride↗