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Biomedical subjects

R Austgulen

Publications and source records attributed to R Austgulen.

At least 55 records · Page 3Linked to original sources
PubMed1992

Expression of receptors for tumor necrosis factor in human placenta at term.

The biological effects of tumor necrosis factor (TNF) are mediated through its interaction with high affinity receptors on target cells. Secretion of soluble cytokine receptors has been suggested as a mechanism of regulating cytokine activity in vivo. In a previous study we detected soluble TNF receptors (TNFRs) in amniotic fluid and urine samples from pregnant women, suggesting that secretion of soluble TNFRs may provide a mechanism for protection of the fetus against TNF action during pregnancy. In the present study, TNFR containing cells in cryostat sections from normal placentas at term were evaluated by monoclonal antibodies against the 55 kD--and the 75 kD TNFR in an indirect immunofluorescence technique. The 55 kD TNFR was expressed by the villous syncytiotrophoblasts, by vascular endothelial cells, by some decidual cells and by occasional cells in the placental stroma. Staining for the 75 kD TNFR was confined to the vascular endothelial cells, a relatively small number of stromal cells and decidual cells, whereas the villous syncytiotrophoblasts were negative. The abundant expression of TNFRs in placental tissue suggests: 1. That a considerable number of the placental cells are receptive to the regulatory activities of TNF; 2. That placental cells may be the cellular origin of soluble TNFRs secreted during pregnancy.

Antibodies, Monoclonal↗
PubMed1990

Treatment of refractory aplastic anemia with plasmapheresis: report of a case in childhood with review of the literature.

Treatment of aplastic anemia may raise considerable problems in some patients. This report concerns a boy whose illness started at 11 years of age. At first admission laboratory data were: hemoglobin 7.5 g/l, and counts of leucocytes, neutrophils and platelets were 2.3, 0.6, and 8 x 10(9)/l, respectively. His bone marrow was hypoplastic with sparse erythropoiesis. The patient did not respond to traditional medical treatment. Serum contained a high concentration of erythropoietin but no antibodies against erythropoietin. The patient's serum did neither alone, nor supported with recombinant erythropoietin, stimulate erythropoiesis in a bioassay, suggesting that some factor(s) inhibiting erythropoietic activity was present. Based on this hypothesis, plasma exchange was performed. After 26 weeks of plasmapheresis the hematological parameters were normalized. We conclude that plasmapheresis might be an alternative in treatment of resistant aplastic anemia. Further diagnostic tools to identify patients who might benefit from such a treatment are required.

Anabolic Agents↗
PubMed1989

Tumor necrosis factor-induced expression of platelet-derived growth factor A-chain messenger RNA in fibroblasts.

Recombinant tumor necrosis factor (rTNF) induced a transient increase in the expression of the PDGF A-chain mRNA in FS-4 fibroblasts, as determined by Northern blot hybridization. The mRNA transcripts were of the expected sizes 1.9, 2.3, and 2.8 kb. Increased levels of the PDGF A-chain mRNA were detected 1, 2, and 4 h after addition of rTNF, the highest level being detected after 2 h. After 8 h the mRNA level was similar to that in control cultures. No PDGF B-chain mRNA (c-sis) could be detected following addition of rTNF. There was also an accumulation of PDGF receptor-competing activity in the medium of rTNF-exposed fibroblasts, suggesting that rTNF also induced the synthesis and release of functional PDGF A-chain homodimers (PDGF-AA). The fibroblast growth stimulatory activity in supernatants from rTNF-exposed fibroblasts could be neutralized by antiserum against rTNF, and thus rTNF seemed to be able to act as a direct mitogen. Hence rTNF-induced PDGF-AA is not the main mediator of rTNF's mitogenicity under the conditions investigated.

Binding, Competitive↗
PubMed1989

Evidence that tumor necrosis induced by aminated beta 1-3D polyglucose is mediated by a concerted action of local and systemic cytokines.

Aminated beta 1-3D polyglucose (AG) causes regression of Meth A sarcoma in syngeneic mice when injected systemically on day 7 after tumour inoculation. AG does not concentrate in the tumour, but distributes throughout the body. AG treatment causes release of large amounts of interleukin 1 (IL-1) both in vivo and in macrophage cultures in vitro. AG is a weak stimulus for tumour necrosis factor (TNF) release both in vitro and in vivo. However, tumour tissue and sera from untreated mice on days 3 and 7 after inoculation contain significant amounts of TNF, whereas tumour tissue and sera on day 14 contain insignificant amounts of TNF. This correlates exactly with the sensitivity to AG treatment. IL-1, and TNF when injected locally cause reduction in tumour blood circulation and also shrinkage of the tumour. All these facts taken together indicate that the tumour circulatory failure and necrosis induced by AG are mediated by local TNF-unrelated to the treatment--potentiated by systemic cytokines triggered by the AG.

Animals↗
PubMed1989

[Factors influencing hematopoiesis--a new therapeutic alternative?].

Hematologic growth factors are now assessible in recombinant forms, and thus available in amounts making cliical use possible. Erythropoietin, which induces differentiation and proliferation of the red blood cells, is produced by recombinant techniques. Clinical trials have shown the effectiveness of erythropoietin in correcting the anaemia of end stage renal diseare in patients maintained by haemodialysis. One of the growth factors for white blood cells, so called colony stimulating factors (CSF) has been given to patients suffering from AIDS. The growth factor given (GM-CSF) has a stimulatory effect upon granulocytes as well as monocytes. The clinical trial showed that the low white cell counts of the patients were normalized in a dose-dependent manner after GM-CSF administration. Clinical studies are under way. Erythropoietin, GM-CSF and G-CSF (stimulates granulocytes) are now being tested at medical centers in patients with AIDS, various forms of anemia, cancer and bone marrow transplants.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Synergistic growth-inhibitory activity of tumour necrosis factor and alpha interferon. Contribution to the monocyte-derived cytostatic activity towards human leukaemia K562 cells.

Monocyte supernatants are cytotoxic towards WEHI 164 clone 13 cells and cytostatic towards K562 cells. The cytotoxic activity towards the clone 13 cells is entirely due to tumour necrosis factor alpha (TNF alpha), since it was completely neutralized by recombinant TNF alpha (rTNF) antiserum, and identical dose-response curves were obtained with supernatants and rTNF alpha. The cytostatic activity towards the K562 cells, however, was only partly due to TNF alpha, since this activity was only partly neutralized by the rTNF alpha antiserum. Moreover, the supernatants were found to be more cytostatic towards K562 cells than rTNF alpha preparations that contained comparable amounts of TNF. Alpha interferon (IFN-alpha) also contributed to cytostasis of the K562 cells, since antibodies against IFN-alpha partially inhibited the cytostatic activity in the supernatants, and further inhibition, although not complete, was obtained in the presence of both IFN-alpha antibodies and rTNF alpha antiserum. Moreover, recombinant IFN-alpha-2c (rIFN-alpha-2c) inhibited the growth of K562 cells, acting synergistically with rTNF alpha. Upon cation exchange chromatography, natural TNF in the monocyte supernatants eluted more broadly than rTNF, and significant amounts of TNF alpha were found in all column fractions containing cytostatic activity.

Cell Survival↗
PubMed1988

A physico-chemical comparison of the monocyte-derived fibroblast growth factor and the tumour necrosis factor.

The chromatographic characteristics of the human monocyte-derived growth stimulatory activity towards diploid FS-4 human fibroblasts has been studied. The fibroblast growth stimulatory factor had an apparent isoelectric point of 5.8 as determined by chromatofocusing, and a molecular weight in the range 70,000-30,000 as determined by gel filtration. The growth stimulatory factor eluted together with the tumour necrosis factor (TNF) upon cation exchange chromatography, chromatofocusing and gel filtration. Moreover, the fibroblast growth stimulatory activity in crude monocyte supernatants as well as the activity in the gel filtration column fractions was neutralized by antiserum raised against recombinant TNF (rTNF). The results indicate that the monocyte-derived fibroblast growth stimulatory activity is largely due to TNF.

Cell Line↗
PubMed1988

Involvement of tumor necrosis factor in cytotoxicity mediated by human monocytes.

Human monocytes cultured in a specially prepared medium free of lipopolysaccharide (LPS) constitutively produced a small, though significant, amount of tumor necrosis factor (TNF). Upon addition of LPS, the amount produced remained constant until the LPS concentration reached 1-10 ng/ml, whereupon the production of TNF dramatically increased, eventually becoming 100-fold greater than when the LPS concentration was below 1 ng/ml. Priming the monocytes with recombinant interferon-gamma (rIFN-gamma) before LPS exposure resulted in a 2- to 10-fold increase in TNF production, the highest relative increase being obtained at lower LPS concentrations and in the absence of LPS. Monocyte-produced TNF appears to be the effector molecule in monocyte-mediated killing of some target cell types, since antiserum against recombinant TNF inhibited killing of both actinomycin D-treated and untreated WEHI 164 cells by human monocytes. However, it also appears that TNF may not in all cases be an effector molecule in monocyte-mediated killing, since cytolysis of K562 cells mediated by IFN-gamma/LPS-activated monocytes was not inhibited by antiserum against recombinant TNF. Antiserum which was raised against a monocyte-derived cytotoxic factor and which neutralized recombinant TNF did, however, inhibit monocyte-mediated cytolysis of K562 cells, suggesting that an extracellular factor, perhaps related to TNF, was also involved in monocyte-mediated killing of K562 cells. A TNF-like activity was associated with the monocyte surface membrane, since paraformaldehyde-fixed monocytes expressed cytotoxic activity which was neutralized by antiserum against recombinant TNF. Fixed monocytes activated with rIFN-gamma in addition to LPS before fixation were generally more cytotoxic than those exposed to LPS alone, and those exposed to LPS were much more cytotoxic than those not exposed to LPS. Thus it is possible that high local TNF concentrations may be generated near the target cell upon direct contact between effector and target cells, and that also monocyte-associated TNF may in this way be involved in monocyte-mediated cytotoxicity.

Animals↗
PubMed1987

Comparison of recombinant tumor necrosis factor and the monocyte-derived cytotoxic factor involved in monocyte-mediated cytotoxicity.

A direct comparison of recombinant tumor necrosis factor (rTNF) and the monocyte-derived cytotoxic factor (CF) which is involved in monocyte-mediated cytotoxicity revealed immunological, physiochemical, and biological similarities, indicating that TNF is an effector molecule in monocyte-mediated cytotoxicity. Neutralizing antiserum raised against rTNF completely inhibited the ability of CF-containing monocyte supernatants to induce cytolysis and cell death of sensitive target cells and, conversely, antiserum raised against purified CF completely inhibited the cytotoxic activity of rTNF. Both CF and rTNF have an apparent isoelectric point of 5.8-5.9 as determined by chromatofocusing, and a molecular weight of about 40,000 as determined by gel filtration. Moreover, when present in monocyte supernatants with a total protein concentration of about 1 mg/ml and 0.1% sodium dodecyl sulfate, both CF and rTNF migrated with a molecular weight of about 35,000 upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Pure rTNF, however, migrated with a molecular weight of 17,000, suggesting that the relative amount of sodium dodecyl sulfate to protein is critical for dissociating the apparent dimeric structure of TNF. CF and rTNF were also similar with respect to their ability to kill various types of target cells the sensitivity of which to TNF differ, and the dose-response curves of cytotoxicity obtained with CF-containing monocyte supernatants and rTNF were similar. As is the case with anti-CF serum, anti-rTNF serum inhibited drug-dependent cellular cytotoxicity and cytolysis mediated by both freshly isolated monocytes and in vitro cultured unactivated and lymphokine-lipopolysaccharide activated monocytes, indicating that TNF is an effector molecule in both drug-dependent cellular cytotoxicity and "classical" monocyte-mediated cytotoxicity.

Animals↗
PubMed1987

In vitro cultured human monocytes release fibroblast proliferation factor(s) different from interleukin 1.

Human monocytes cultured in vitro released factors with growth stimulatory effect upon human dermal fibroblasts. Monocytes in RPMI 1640 released a growth enhancing activity in nearly constant amounts during in vitro differentiation to macrophage-like cells. The growth stimulatory effect mediated by supernatants was reduced when lipopolysaccharide (LPS) or opsonized zymosan particles (OpZ) were added to monocytes during the first 5 days of in vitro culture, thereafter reaching similar levels. The release of interleukin 1 (IL-1) from monocytes was restricted to the first 2 days of culture. IL-1 production by unstimulated monocytes was negligible, while LPS induced a high release of IL-1 from monocytes. A rabbit antibody against human IL-1 abolished the IL-1 activity of the monocyte supernatants as assessed in a mouse thymocyte proliferation assay, but caused only a small reduction of the fibroblast proliferation activity. Thus, the fibroblast growth stimulatory activity mediated by monocytes was caused by factor(s) in addition to IL-1.

Cell Differentiation↗
PubMed1987

Monocyte-derived influence on growth of normal human fibroblasts. The contribution of tumour necrosis factor to growth inhibition.

The current study demonstrates that whereas high concentrations of recombinant tumour necrosis factor (rTNF, 0.05 microgram/ml) induced enhanced growth of normal human fibroblasts, supernatants from human monocytes with a similar TNF concentration induced cytostasis. This cytostasis was inhibited by an antiserum against rTNF. The TNF activity, measured as cytotoxicity against TNF-sensitive WEHI 164 cells, cochromatographed with the fibroblast growth inhibitory activity upon ion-exchange chromatography of monocyte supernatants. This indicates that TNF contributes to the fibroblast growth inhibition mediated by monocyte supernatants. Alpha interferon (IFN-alpha) abolished the growth of fibroblasts induced by rTNF, whereas rTNF in combination with gamma interferon (IFN-gamma) inhibited growth of fibroblasts. The interferon activity in the supernatants was determined to find out whether the growth-inhibitory activity of natural TNF was due to interferons present in the monocyte supernatants, which might modulate the TNF activity. Cytostasis of fibroblasts was mediated by monocyte supernatants which did not contain IFN-gamma in significant amounts. All supernatants contained IFN-alpha. An antiserum against IFN-alpha partially reduced the cytostasis induced by monocyte supernatants. This cytostasis was totally abolished by rTNF antiserum, suggesting that IFN-alpha modulates the growth-inhibitory activity of TNF in the monocyte supernatants. It appeared that the different effects of recombinant and natural TNF on fibroblast growth can probably not be attributed to monocyte-derived TNF-modulating factors alone. Thus, recombinant and natural TNF may differ in a way that affects their capacity to induce cytostasis of normal fibroblasts.

Cell Division↗
PubMed1987

Lymphotoxin-induced growth stimulation of diploid human fibroblasts in the presence and absence of gamma interferon.

In the present study we investigated the effect of lymphotoxin (LT) on the growth of human diploid fibroblasts, in the presence and absence of gamma interferon (IFN-gamma). Recombinant LT (rLT) had a growth stimulatory effect on diploid human FS-4 fibroblasts. This growth-stimulatory effect was reduced in the presence of recombinant IFN-gamma (rIFN-gamma). LT thus has a similar effect on diploid fibroblasts as tumour necrosis factor (TNF).

Cell Division↗
PubMed1987

Fibroblast growth-stimulatory activity released from human monocytes. The contribution of tumour necrosis factor.

Human monocytes release fibroblast growth-stimulatory activity. In this study tumour necrosis factor (TNF) has been identified as a major contributor to the monocyte-derived fibroblast growth-stimulatory activity. A neutralizing monoclonal antibody (MoAb) against recombinant TNF (rTNF) inhibited growth of FS-4 fibroblasts and skin biopsy fibroblasts induced by monocyte supernatants, indicating that TNF was involved in the stimulation. Optimal growth of FS-4 fibroblasts was induced by monocyte supernatants at dilutions which contained TNF at a concentration between 1.6 X 10(-6) and 4.0 X 10(-5) micrograms/ml, less growth being induced at higher TNF concentrations. Contrary to this, no optimal concentration interval was found for rTNF, since increasing rTNF concentrations always resulted in increased growth stimulation. It also appeared that natural TNF in the monocyte supernatants induced growth at a much lower concentration than rTNF tested in the absence of monocyte supernatant.

Antibodies, Monoclonal↗
PubMed1986

Human monocyte-released cytotoxic factor: effect on various cellular functions, and dependency of cytolysis on various metabolic processes.

The ability of the human monocyte-released cytotoxic protein factor(s) (CF) to mediate cytolysis when various metabolic processes in target cells were inhibited, and its effect on various cell functions have been studied. Cytolysis was reduced when target cells were exposed to either chloroquine or colchicine, indicating that lysosome function and the formation of microtubule are of importance with respect to the interaction between CF and target cells, possibly by effecting internalization and processing CF and its receptor. A decrease in the energy charge of the target cells did not affect the ability of CF to mediate cytolysis, since the 60-70% reduction of the cellular ATP content by uncoupling oxidative phosphorylation had little effect on CF-induced lysis. It was unnecessary for target cells to be actively growing and dividing for CF to induce lysis because inhibition of cellular protein, RNA, and DNA synthesis potentiated the cytolytic effect of CF. CF-induced cell lysis of Walter and Eliza Hall Institute (WEHI) 164 target cells was first detected between 3.0 and 4.5 hr after addition of CF. Target cell DNA synthesis nearly terminated within 3-4 hr, about the time of first cell lysis detection. Compared to the effect on DNA synthesis, the CF effect on protein synthesis was negligible and only a slight reduction was detected in the RNA synthesis and in the cellular ATP content. The results indicated that the DNA-synthesizing machinery may either be a primary target site of CF or a rapid influence of CF action on its primary target site; however, neither the protein- or RNA-synthesizing machinery nor the cellular ATP generating systems are likely to be primary target sites.

Adenosine Triphosphate↗
PubMed1986

WEHI 164 sarcoma cells rendered resistant to monocyte-released cytotoxin are also resistant to monocyte-induced cytolysis.

WEHI 164 sarcoma cells cultured with monocyte-released cytotoxin (CF) for 4 weeks became resistant to CF-induced cytolysis and were concomitantly rendered resistant to monocyte-induced cytolysis. The resistant cell line (R-WEHI 164) has been stable with respect to resistance to monocyte- and CF-induced lysis for more than 7 months. WEHI 164 and R-WEHI 164 cells adsorbed CF and no significant difference in CF adsorption was observed. The results indicate that CF may be an effector molecule in monocyte-mediated cytolysis.

Adsorption↗