The interferon-interleukin 1 connection.
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Animals↗
Biomedical subjects
A Billiau
Publications and source records attributed to A Billiau.
Homogeneous interferon-beta-inducing 25K factor (IL-1 beta) has connective tissue cell stimulating activities.
The human interferon-beta-inducing 22K factor has been shown to have structural homologies with interleukin-1 beta (IL-1 beta) and some of the activities attributed to IL-1. We have shown that 22K factor, purified to homogeneity and endotoxin free, has connective tissue cell stimulating activities, indicating that these activities are due to a naturally occurring species of IL-1 beta and not contaminating factors. 22K factor stimulated the production of prostaglandin E, caseinase activity and plasminogen activator activity in human articular chondrocytes in culture. This cell system appears highly sensitive to 22K factor activity. 22K factor also stimulated the resorption of bovine nasal cartilage and neonatal mouse calvaria.
Animals↗
Phorbol ester stimulates the synthesis and phosphorylation of a 48 kDa-intracellular protein in plasminogen activator secreting melanoma cells.
Phorbol ester (12-O-tetradecanoyl-phorbol 13-acetate) stimulates the secretion of tissue-type plasminogen activator by the melanoma cell line, Bowes. This effect is associated with increased levels of mRNAs for both tissue-type plasminogen activator and a 48 kDa-protein. Labelling of melanoma cells with L-[35S]methionine allowed to identify an intracellular protein which, by 3 criteria, was identical with the in vitro translation product of the 48kDa-protein mRNA: a Mr of 48,000 on electrophoresis in the presence of sodium dodecyl sulphate; inducibility by phorbol ester and failure of reducing agents to affect electrophoretic mobility. As detectable by L-[35S]methionine labelling, the protein was mainly localized in the cytosol. In vitro phosphorylation reactions, carried out on subcellular fractions revealed a membrane-associated protein which also had the three characteristics of the aforementioned 48 kDa-protein. Phosphorylation did not require Ca2+-ions. Addition of phorbol ester to the reaction mixtures increased the phosphorylation. Reconstitution experiments between membrane and cytosol fractions of phorbol ester-treated and untreated cells showed that the 48kDa protein occurs in a cytosolic, unphosphorylated and a membrane-bound, phosphorylated form and that the former is converted to the latter by a phorbol ester activated, membrane-associated protein kinase.
Cell Line↗
Messenger RNA for a phorbol-ester induced 48,000 dalton protein from human melanoma cells.
Messenger RNA of the phorbol ester-induced 48kDa protein from human melanoma cells (Bowes) was isolated, characterized and used to study the protein processing. The 48kDa mRNA is induced simultaneously with that of tissue-type plasminogen activator. This induction is prominent as shown by sedimentation profiles on linear sucrose gradients. The mRNA can be isolated by classical phenol extractions, has a poly(A)-tail and sediments with a coefficient of 20 S. Translation in reticulocyte lysates yields a 48kDa protein whether the translation is modified with canine pancreas microsomal membranes or not. Analysis of 48kDa mRNA translation products by sodium dodecyl sulphate/polyacrylamide gel electrophoresis showed that the phorbol ester-induced 48kDa is a monomeric one-chain polypeptide. Glycosylation could not be detected, nor signal peptide cleaving, suggesting that it is a non-secreted intracellular protein.
Animals↗
Human rhinovirus protein synthesis and polyprotein cleavage in infected HeLa-RH cells. Brief report.
Precursor and mature polypeptides of four human rhinovirus types (HRV 30, 63, 81 and 88) were compared. The SDS-PAGE profiles of the HRV-specific polypeptides differed significantly from each other, as well as from those of the HRV types studied previously (HRV 1A, 2 and 14). Our results provide further evidence for considerable heterogeneity within the rhinovirus genus.
HeLa Cells↗
Production and partial purification of human immune interferon induced with concanavalin A, staphylococcal enterotoxin A, and OK-432.
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Biological Products↗
Production and purification of mouse immune interferon.
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Animals↗
The interferons: a brief introduction.
Interferon has been known for a long time but until recently, it was defined simply as a complex of proteins with antiviral activity that occurs when cultured cells are infected by virus. Significant progress has been made in the study of interferons. This article presents the properties of interferon and its mechanism of action, and the use of animal model systems to study interferon.
Animals↗
The mode of action of interferons in viral infections and their possible role in the control of hepatitis B.
Interferons can alter the course of virus infections by inhibiting virus replication at the intracellular level and by modifying the aspecific and specific immune response to viral antigens in body fluids and on cellular surfaces. Treatment of isolated cells with interferon renders them resistant to infections by viruses belonging to virtually any family. Knowledge of the mechanism of this effect is derived from studies employing both DNA (especially vaccinia virus and SV40) and RNA-viruses (especially picorna-, toga-, rhabdo-, reo- and retroviruses). Interferon induces multiple alterations in the level and state of intracellular regulatory molecules, leading to inhibition of virus replication at several possible steps. In the case of certain DNA viruses, transcription of viral DNA seems to be inhibited. In the case of RNA viruses the target for interferon action is mainly translation. The retroviridae constitute a special case and, in view of their analogy with the hepadnaviridae, are of particular relevance to the possible effects of interferon on the replication of HBV. Interferon inhibits one or more initial stages of primary infection of cells by transforming or nontransforming retroviruses, thereby preventing or delaying the synthesis and/or integration of viral DNA. In cells that already contain an integrated and fully expressed retrovirus genome, interferon treatment results in a reduced release of viral particles as well as a downward shift of the ratios between the numbers of infectious vs noninfectious particles. Immuno-modulatory properties of interferon which might alter the course of HBV-infection include: potentiation of cytotoxic activity of lymphocytes and macrophages; direct anti-inflammatory effects; enhancement or depression in antibody formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Interleukin 1 as a cytokine inducer.
Human interleukin 1 (IL 1) exerts an interferon-like antiviral activity in certain strains of human diploid fibroblasts. It is shown that this antiviral effect is indirect, in that it is mediated by production of interferon-beta. IL 1 also induces synthesis of the mRNA of another secreted protein, 26K, whose biological function is still controversial. Finally, IL 1 has bone marrow colony stimulating activity which is shown to be due to induction of colony stimulating factor in adherent phagocytic cells present in the bone marrow cultures. These findings emphasize the concept that several of the varied biological effects of IL 1 may be indirect.
Bone Marrow Cells↗
Epidemic spastic paraparesis in Bandundu (Zaire).
Epidemiological findings of twenty sporadic cases of epidemic spastic paraparesis (buka-buka) in three areas of Bandundu (Zaire) are reported. These findings suggest the involvement of an infectious agent and do not support the hypothesis of a dietary cyanide intoxication, which has been advanced to explain the outbreak of a very similar disease (Mantakassa) in Mozambique.
Adult↗
Influence of carbohydrate side chains on activity of tissue-type plasminogen activator.
When messenger RNA (mRNA) from both untreated and phorbol ester-treated melanoma cells is translated in simple reticulocyte lysates, tissue-type plasminogen activator can be immunoprecipitated by an affinity-purified antibody as a approximately 52,000 mol wt protein, with no detectable biological (plasminogen activating) activity. When the reticulocyte lysate system is supplemented with a preparation of microsomal membranes, biological activity becomes detectable and a 63,000 mol wt protein can be immunoprecipitated with the same antibody. Furthermore, when natural tissue-type plasminogen activator (mol wt approximately equal to 70,000) is incubated with different glycosidases, distinct alterations in the electrophoretic mobility of the molecules are observed, together with alterations in the level of biological activity. While treatment with neuraminidase and beta-galactosidase caused decreases in activity, alpha-mannosidase caused an increase. These results suggest that the carbohydrate part of the molecule can influence its biological behavior.
Amides↗
The interferon system as a basis for antiviral therapy or prophylaxis.
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Animals↗
Cloning of cDNA coding for human tissue-type plasminogen activator and its expression in Escherichia coli.
cDNA clones of the mRNA coding for tissue-type plasminogen activator (t-PA) have been obtained and their nucleotide sequences compared to those reported previously. A gene coding for t-PA has been reconstructed and inserted into vectors for expression in prokaryotic cells. Relatively high levels of t-PA accumulated in inclusion bodies in Escherichia coli containing an optimized expression plasmid, but only a small proportion of the insoluble protein was recovered as active enzyme using a variety of solubilization procedures.
Amino Acid Sequence↗
Pyrogenic and haematological effects of the interferon-inducing 22K factor (interleukin 1 beta) from human leukocytes.
Human 22K factor is a cytokine released by mitogen-stimulated peripheral blood leukocytes. The factor stimulates fibroblasts to produce interferon-beta (IFN-beta) and thereby exerts antiviral activity on these cells. It was identified as interleukin-1 beta (IL-1 beta) by its amino-acid sequence and spectrum of biological activities. The pyrogenic and haematological effects of pure 22K factor were studied at different doses and were compared with those of endotoxin and interferon. 22K factor dose-dependently induced fever in rabbits, 0.1 microgram/kg being a minimum effective dose. Intravenous injection in rabbits caused immediate granulocytosis at low dose, while a profound granulopenia followed by hypergranulocytosis was observed at high dose. Preparations of pure 22K factor were free of detectable lipopolysaccharide and lost their biological effects after heat-treatment. Repeated injections of 22K factor did not result in a state of tolerance. There is no evidence that the effects in vivo of 22K factor were mediated by induction of interferon. Human 22K factor, a weak and species-specific inducer in IFN-beta in vitro, did not induce detectable amounts of circulating interferon in rabbits. Moreover, injection of rabbits with IFN-beta resulted in a weak effect on body temperature and granulocyte counts as compared to similar doses of 22K factor.
Agranulocytosis↗
Interleukin-1 (22-K factor) induces release of granulocyte-macrophage colony-stimulating activity from human mononuclear phagocytes.
An electrophoretically pure preparation of natural human interleukin-1 (IL-1) was shown to stimulate in vitro colony formation in human bone marrow cultures. Day 4 myeloid cluster-forming cells (CFC), as well as early (day 7) and late (day 10) granulocyte-macrophage colony-forming units (CFU-GM) were stimulated in a dose-dependent fashion. At optimal concentrations of IL-1, the number of day 4 CFC reached 72%, the number of day 7 CFU-GM reached 32%, and the number of day 10 CFU-GM reached 80% of the respective numbers of colonies obtained by addition of crude leukocyte-conditioned medium (LCM). The IL-1-induced stimulatory effect on CFU-GM growth could be completely neutralized by a rabbit anti-IL-1 antiserum. Colony growth was abrogated by depleting the marrow cell suspensions of phagocytic cells prior to IL-1 addition. Conversely, the effect could be reintroduced by addition of marrow-derived adherent cells to bone marrow cell suspensions that had been depleted of both phagocytic and E rosetting T cells. Furthermore, media conditioned by bone marrow-derived adherent cells or by peripheral blood mononuclear phagocytes in the presence but not in the absence of IL-1, stimulated in vitro colony growth of phagocyte-depleted bone marrow cell suspensions. These results indicate that IL-1 induces release of granulocyte-macrophage colony-stimulating activity (GM-CSA) from human mononuclear phagocytes.
Bone Marrow↗
Determination of tissue-type plasminogen-activator mRNA in human and non-human cell lines by dot-blot hybridization.
A labelled cDNA clone was used in DNA-RNA hybridization on nitrocellulose filter paper (dot-blot technique) to detect and quantify mRNA for endogenous tissue plasminogen activator (PA) in cell extracts and samples of RNA purification runs. Although, for detection purposes, the assay was less sensitive than translation in Xenopus oocytes, it was at least as reliable and much more convenient for the purpose of quantitative determination. In particular, the technique was used to study the kinetics of PA mRNA formation in a human melanoma cell line (Bowes) after exposure to the tumour promoter 12-O-tetradecanoylphorbol 13-acetate (TPA). Incubation of the cells with TPA resulted in a 15-20-fold increase in cellular PA mRNA content. The effect was time- and dose-dependent: the increase in PA-specific mRNA was clearly visible as early as 4 h after initiation of TPA treatment in Bowes cells. It was blocked completely by pretreatment of the cells with actinomycin D, indicating that TPA caused enhancement of synthesis of PA mRNA rather than inhibition of PA mRNA degradation. The use of the nitrocellulose dot-blot technique also revealed that two non-human cell lines produce mRNAs which cross-react with the human PA mRNA, namely the mouse melanoma cell line B16 and the rat brain-tumour cell line, RT4-71-1. TPA was found to exert similar stimulatory effects on the synthesis of mRNAs in these cell lines as in Bowes cells.
Animals↗
Induction of a 26-kDa-protein mRNA in human cells treated with an interleukin-1-related, leukocyte-derived factor.
A human-leukocyte-derived antiviral protein (22-kDa factor), known to be an inducer of interferon-beta (IFN-beta) in fibroblastoid cells, and to be closely related to interleukin-1 (IL-1), was shown to likewise act as inducer of the mRNA of a 26-kDa secreted protein. This protein was first described as the gene product of an mRNA that is co-induced with the mRNA of IFN-beta by superinduction of fibroblasts (treatment with dsRNA and cycloheximide). Subsequently it was shown to be induced by treatment with cycloheximide only. The 22-kDa factor induced high levels of the 26-kDa-protein mRNA and low levels of IFN-beta mRNA. Addition of cycloheximide to the 22-kDa factor resulted in further significant increases in mRNA levels for both the 26-kDa-protein and IFN-beta. These observations add to the evidence already available that transcription of the genes for IFN-beta and the 26-kDa-protein are differently regulated. The observation that a factor that belongs to the IL-1 family induces the 26-kDa-protein suggest that the latter plays a role as an intermediary or effector molecule in inflammatory or immunoregulatory processes.
Cell Line↗