On the role of endogenously produced TNF-alpha and IL-6 as regulators of growth and differentiation of B-type chronic lymphocytic leukemia cells in vitro.
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Cell Differentiation↗
Biomedical subjects
K Nilsson
Publications and source records attributed to K Nilsson.
BCL-2 in B-chronic lymphocytic leukemia.
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Antigens, CD↗
A novel mutation in the beta-protein coding region of the amyloid beta-protein precursor (APP) gene.
A novel mutation, a C to T transition at base pair 2124 in exon 17 of the amyloid beta-protein precursor (APP) gene, has been identified by direct sequencing of amplified DNA from two Alzheimer's disease (AD) patients. A simple oligonucleotide-hybridization procedure was developed to allow population studies of this DNA variation. The mutation, which is silent at the protein level, was present in 2 out of 12 investigated AD patients, in 1 out of 60 non-AD patients and in 1 out of 30 healthy individuals. The mutation can be used as a new marker for linkage studies involving the APP gene, although more comprehensive population studies are required to determine the status of the mutation as a possible risk factor for the development of AD.
Alzheimer Disease↗
Low-dose oestradiol in the treatment of urogenital oestrogen deficiency--a pharmacokinetic and pharmacodynamic study.
Twenty-four postmenopausal women with vaginal atrophy due to oestrogen deficiency were treated with 17 beta-oestradiol administered as vaginal tablets containing 10 and 25 micrograms, respectively, in a slow-release system (Vagifem, Novo Nordisk, Denmark). All the women were treated for 2 weeks with each dose in a double-blind, cross-over study. Plasma concentrations of unconjugated oestradiol and unconjugated oestrone were measured at regular intervals for 24 h on days 1 and 14 of each treatment regimen. Cytological and clinical evaluations of the vaginal and urethral epithelium were also carried out. Initially, when the epithelium was still atrophic, dose-dependent absorption of oestradiol was demonstrated. After 14 days of treatment maturation of the vaginal epithelium was seen with both regimens and the absorption of oestradiol then declined significantly on both the 10 and the 25 micrograms dose. Oestrone levels remained unchanged and gonadotrophin levels were unaffected during treatment. Vaginal cytology showed maturation on both the 10 and the 25 micrograms dose, whereas urethral cytology showed a reduction in parabasal cells that was significant only on 25 micrograms. Clinical and subjective improvement was apparent on both doses and acceptance of treatment was good.
Administration, Intravaginal↗
Effects of tobacco-smoke on radiation-induced pneumonitis in rats.
To investigate the effect of exposure to tobacco smoke (TS) on the development of irradiation-induced pneumonitis in rats, five groups of animals were investigated including controls (C), tobacco smoke exposed (S), irradiated (RNS) and irradiated and tobacco smoke exposed (RS). An additional group (RS/NS) was exposed to tobacco before irradiation but not afterwards. Rats were exposed to diluted mainstream cigarette smoke at a concentration of about 0.4 mg/l in a nose-only exposure system for 1/day, 5 days/week for 10 weeks. Exposure to TS started 3 weeks before irradiation in which the basal one-third of both lungs was exposed to a single dose of 28 Gy. In previous studies this dose had been shown to cause significant pneumonitis. All the animals were killed at 7 weeks after irradiation. Examination of the morphology of lung sections showed less pulmonary inflammation in the RS group than in the RNS group. This was also reflected in the results of bronchoalveolar lavage (BAL) which showed a decline in cell recovery and a marked decrease in the numbers of mast cells and neutrophils in the RS rats compared with the RNS animals. The concentration of hyaluronan in lavage fluid was increased in the RNS and RS/NS group while no increase was found in the RS group. A marked increase in BAL protein was also seen in the RNS and RS/NS groups as compared with the RS group but all were significantly higher than in unirradiated controls. This indicates that smoking suppresses the radiation-induced inflammation but to a lesser degree affects the radiation-induced increase in membrane permeability as reflected by increased protein levels in BAL. Moreover, the marked effects on the numbers of mast cells and neutrophils in the RS group may indicate that these cells play an important role in the mechanism by which tobacco smoke modulates the effects of irradiation. When exposure to tobacco smoke was terminated immediately after irradiation (RS/NS), the inflammatory response was unaffected.
Animals↗
Peroxisome proliferation and resistance to hydrogen peroxide in rat hepatocytes: is development of resistance an adaptation to cytotoxicity?
In this work the resistance of peroxisome-proliferated hepatocytes to hydrogen peroxide (H2O2) has been studied. The question has been raised as to whether this resistance is a response to cytotoxicity. In an initial series of experiments, hepatocytes were isolated from rats that had been treated with nafenopin (NAF-hepatocytes). Isolated cells were exposed to a H2O2-generating system or to H2O2 in pulses. The ability to attach to collagen was used as a toxicological endpoint. Loss of attachment was found to be correlated to glutathione (GSH) depletion, and NAF-hepatocytes were more resistant to GSH depletion and to loss of attachment induced by H2O2 than were control hepatocytes. NAF-hepatocytes were not resistant to hydroquinone or to adriamycin. It was also indicated that this resistance was related to an altered metabolism of H2O2, less dependent on GSH. In a second series of experiments, hepatocytes from altered hepatic foci-bearing rats, treated with nafenopin or di(2-ethylhexyl)phthalate (DEHP), were used. This model was used in an attempt to monitor the development of resistance in different subpopulations of hepatocytes. It was found that the majority of hepatocytes developed resistance towards H2O2, and that, for example, foci marker-positive hepatocytes were as resistant as marker-negative cells. In control experiments with this model, it was found that marker-positive cells were more resistant towards diethyl maleate (DEM) or phorone than were marker-negative cells. In addition to demonstrating the validity of the model, these control experiments indicate an increased steady-state level of H2O2 in cells from peroxisome proliferator-treated rats. Other control experiments suggested that a low GSH-peroxidase activity protected from, rather than aggravated, the effect of peroxisome proliferation on marker-negative and GSH-depleted cells. It is concluded that H2O2 metabolism may affect the function of collagen receptors, but that a shift in H2O2 metabolism, so that it becomes less dependent on GSH, conferred resistance to this effect. The apparent non-focal induction of resistance to peroxisome proliferators, as opposed to the focal induction of resistance induced by most liver carcinogens, may explain the lack of development of gamma-glutamyltranspeptidase-positive foci in peroxisome proliferator-treated rats.
Adaptation, Physiological↗
SDZ PSC-833--a novel potent in vitro chemosensitizer in multiple myeloma.
Multiple myeloma cell lines and patient tumor samples with and without the expression of the classical multidrug resistance (MDR) phenotype were investigated in vitro for drug induced cytotoxicity and modulation of drug resistance. Overall there was a good correlation in the cell lines between MDR expression, as measured by immunocytochemistry with monoclonal antibodies against P-glycoprotein 170 (Pgp), and in vitro resistance to doxorubicin (dox) and vincristin (vcr). Drug resistance in the cell line RPMI 8226 dox 40, expressing a high level of Pgp, was almost completely reversed by the novel non-immunosuppressive cyclosporin A (CsA) analog SDZ PSC-833 (PSC), while the chemosensitizers verapamil, CsA and quinine, in clinically achievable concentrations, were much less effective. In cell lines with low Pgp expression, PSC and the other chemosensitizers seem equally effective. The patient tumor samples were selected to represent different combinations of Pgp expression, drug resistance and effects of chemosensitizers. PSC and CsA appeared equally potent and resistance modulation was detected not only in Pgp positive, but also in Pgp negative tumor samples. Furthermore, in one case of a Pgp expression myeloma, chemosensitizers were without effect. These findings indicate the need to incorporate in vitro chemosensitivity assays with Pgp determination when the effects of MDR modulating chemosensitizers are to be studied in the clinic.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Pulmonary clearance of 99mTc--DTPA and 99mTc-albumin in rabbits with surfactant dysfunction and lung injury.
We measured the pulmonary clearance of inhaled 99mTc-DTPA and 99mTc-albumin in rabbits with surfactant dysfunction induced by dioctyl sodium sulphosuccinate and in rabbits with lung injury induced by oleic acid. The animals were tracheotomized and mechanically ventilated. After inhalation of 99mTc-albumin in ten animals, clearance of the tracer from the lungs was monitored for 90 min. The first 30 min was a control period. Dioctyl sodium sulphosuccinate was then administered in aerosol and after another 30 min oleic acid was injected intravenously. Ten other rabbits were given 99mTc-DTPA, and clearance was externally recorded for 60 min. Five animals inhaled detergent aerosol and five animals were given oleic acid intravenously after 30 min. Airway pressures, tidal volume, and arterial blood gases were measured before and after each intervention. The half-life of 99mTc-albumin in the lung was 442 +/- 123 min during the control period, 363 +/- 52 min after detergent administration, and 134 +/- 18 min after oleic acid administration (P less than 0.05 compared to control and P less than 0.01 compared to the period after detergent). The half-life of 99mTc-DTPA was 94 +/- 16 min before and 10 +/- 0.6 min (P less than 0.01) after detergent administration and 75 +/- 12 min before and 18 +/- 1.8 min (P less than 0.01) after oleic acid administration. Gas exchange was not affected by administration of dioctyl sodium sulphosuccinate but markedly impaired after injection of oleic acid. Compliance of the respiratory system remained unaffected by detergent but decreased after injection of oleic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Endogenous estrogen levels in postmenopausal women with severe urogenital atrophy.
In order to be able to evaluate the systemic influence of exogenous estrogen therapy in different conditions, it is important to have knowledge of the endogenous estrogen levels. The present study was undertaken to assess the basic levels and possible fluctuations of endogenous estrogen in postmenopausal women with urogenital estrogen deficiency. Plasma concentration levels of unconjugated estrone and estradiol were measured at regular intervals during 24 h in 5 postmenopausal women without estrogen treatment. All women had very low levels of estradiol. No diurnal fluctuation was found. Estrone levels were not measurable with a sensitive RIA technique.
Atrophy↗
Differentiation and activation associated expression of IL-6 and IL-6 receptors in U-937 monocytic cells: relationship to the expression of CD14.
Activated monocytes play an important role as producers of IL-6 during inflammation and immune response. We show that during monocytic differentiation of U-937 cells, induced by phorbolester (PMA), IL-6 mRNA expression was transiently up-regulated and IL-6 protein was secreted into the medium. In contrast, differentiation induced by VitD3 or Retinoic acid (RA) did not lead to an increase in the IL-6 expression. Thus, IL-6 expression does not seem to be associated with monocyte differentiation per se. However, U-937 cells terminally differentiated by VitD3, rapidly responded to bacterial lipopolysaccharide (LPS) induced activation by IL-6 expression and secretion. In cells, differentiated by PMA, the IL-6 expression was super-induced after activation by interferon-gamma (IFN-gamma) and LPS. The capacity of U-937 cells to respond to LPS activation by IL-6 expression was associated with the expression of CD14 and some serum components(s) were a prerequisite for a successful LPS induction. The IL-6R expression was down-regulated during monocytic differentiation of U-937 cells. In the terminally differentiated U-937 cells, the expression of IL-6R could be induced after activation by IFN-gamma and to a lesser extent by LPS, suggesting a mechanism by which activation positively regulates the response to IL-6 in macrophages.
Antigens, CD↗
Control of growth and differentiation of B-type chronic lymphocytic leukemia cells in vitro.
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Cell Differentiation↗
Human B-lymphoid cell lines.
The collective efforts during almost three decades by hematologists, tumor biologists and immunologists have provided a collection of established human hematopoietic cell lines, representing most of the hematopoietic cell lineages. The representativity of cell lines derived from the B cell differentiation lineage, however, is the most impressive. Human B-lymphoid cell lines are extensively used world wide as models in studies of various aspects of B cell biology and as tools in research on the etiology, pathogenesis and the biology of leukemia and lymphoma. Lymphoblastoid cell lines (LCL) carrying the Epstein-Barr Virus (EBV) are of particular importance. These lines can be established spontaneously from blood and lymphoid tissue from any EBV positive individual by special techniques, and from all individuals by EBV infection of peripheral blood B cells by EBV infection in vitro. At spontaneous establishment B cells, latently infected by EBV in vivo, will release EBV which subsequently infects normal EBV-negative B cells and immortalizes them into LCL cells, but direct outgrowth of the latently infected B cells as LCLs has also been documented. The target B cells for the EBV infection in vitro are not fully defined-most are mature B cells but also pro-B and pre-B and some B-blasts can be infected. Apart from their capacity for infinite growth, LCL cells have non-malignant properties, e. g. they are diploid, do not grow in agarose and do not form tumors upon inoculation subcutaneously in nude mice. LCLs have a phenotype corresponding to activated B cells (B-blasts) and have been used as "the E. Coli" of eukaryotic cells for about two decades. LCLs are derived at a high frequency also from tumor biopsies of EBV positive patients with leukemia and lymphoma. However, tumor cell lines are available from most of the B cell lineage-derived leukemias, B-lymphomas and myeloma. The frequency of successful establishment has been particularly high from EBV positive Burkitt's lymphoma (BL). From EBV genome negative BL and other B-lymphoma and B-leukemia biopsies the frequency of successful, spontaneous establishment is low (5-10%), and such lines have, with rare exceptions, been derived from pleural effusions and ascitis of patients with advanced, chemotherapy resistant, disease. Many of the cell lines therefore do not represent the clinically most common types of leukemia and lymphoma. No authentic malignant cell lines have been established from chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL) and Waldenström's disease.(ABSTRACT TRUNCATED AT 400 WORDS)
B-Lymphocytes↗
Molecular investigation of the cytokines produced by normal and malignant B lymphocytes.
Different normal and malignant human B-cell populations were studied with a twofold aim: to define which cytokines are produced in vivo, and to assess the relationship between cytokine production and kinetic state. To analyse normal B-cells representative of different stages of activation and proliferation in vivo, we purified germinal centre (GC)-B blasts and mantle B (M-B) cells from tonsils. To compare malignant B lymphocytes with their closest normal equivalent cells, we separated malignant CD5+B lymphocytes from the peripheral blood of patients with B-chronic lymphocytic leukemia (B-CLL) and normal CD5+B lymphocytes from cord blood. The expression of interleukins (IL) IL-1 alpha, IL-1 beta, tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), IL-2, IL-4, and IL-6 genes was analysed using Northern and Western blotting techniques. TNF-alpha mRNA is produced by resting (M-B) and actively proliferating (GC-B) normal B lymphocytes. TGF-beta mRNA is present at high levels in resting normal M-B cells, while the transcript levels are lower in proliferating GC-B and in activated CD5+B lymphocytes. IL-2 production is limited to the actively proliferating GC-B blasts, IL-1 beta and IL-6 to resting M-B cells. The cytokine production profile of CD5+ malignant B-CLL cells differs from that of their putative normal counterparts and is more like the profile of M-B cells, since B-CLL cells produce IL-1 beta, TNF-alpha, TGF-beta, and IL-6. These observations lead to the following conclusions: among normal B lymphocyte populations, resting M-B lymphocytes are the most active cytokine producers, and B-CLL malignant B cells reflect the production pattern of normal resting B lymphocytes.
Antigens, CD↗
Radiation-induced increase in hyaluronan and fibronectin in bronchoalveolar lavage fluid from breast cancer patients is suppressed by smoking.
Bronchoalveolar lavage (BAL) fluid was analysed from 21 patients with breast cancer, stage T1N0M0, who had undergone tumour resection and post-operative local irradiation (accumulated dose 56 Gy). The lavage was performed two months after radiotherapy, in the anterior part of the lingula (left side) or of the right middle lobe (right side), depending on which side had been exposed to radiation. The patients had significantly increased concentrations of fibronectin (FN) (p less than 0.001), hyaluronan (HA) (p less than 0.01) and albumin (p less than 0.05) in BAL fluid compared with the healthy controls (n = 19). However, when the patients were separated, according to smoking history, it was obvious that the inflammatory reaction occurred entirely in the nonsmoking patient group (n = 10), whilst no difference could be found between the smoking patients (n = 11) and the controls. In the nonsmoking patient group, there was a sevenfold increase in BAL concentrations of FN and a threefold increase in HA. Moreover, four patients had detectable levels of procollagen III peptide in BAL, all were nonsmokers. The smoking habits of the controls had no influence on the BAL measurements. These findings indicate that smoking interferes with the radiation-induced early inflammatory connective tissue reaction of the lung. Finally, the results justify further investigation of interaction of smoking with cancer treatment, both from the view of therapy effectiveness and reduction of adverse effects.
Albumins↗
Increase in interleukin 6 (IL-6) and IL-6 receptor expression in a human multiple myeloma cell line, U-266, during long-term in vitro culture and the development of a possible autocrine IL-6 loop.
A human multiple myeloma (MM) cell line, U-266, has developed the ability to grow independently of exogenous interleukin 6 (IL-6) during long-term cultivation in vitro. The early passage, feeder-cell dependent U-266 cell line (U-266-1970) was compared with the late passage U-266-1984 cell line with respect to response to IL-6, IL-1 beta and tumour necrosis factor alpha and expression of IL-6 and IL-6 receptor (IL-6R) mRNA and protein. The results showed that; (a) only the U-266-1970 cell line was stimulated to growth by IL-6, (b) IL-6 and IL-6R mRNA were expressed in both cell lines, (c) the level of IL-6 mRNA was increased in the U-266-1984 cell line and only this line produced IL-6 and, (d) the level of IL-6R mRNA was highest in the U-266-1984 cell line and the number of IL-6R about ten times higher than in U-266-1970. The growth of the IL-6-producing U-266-1984 cell line was inhibited by 30% by anti-IL-6R antibodies suggesting the possibility that an autocrine IL-6 loop might have developed during the long-term cultivation. In addition to many other phenotypic alterations of the U-266 cell line, having developed as a consequence of tumor progression in vitro, its growth factor requirement seems to have evolved from a dependence on IL-6 as a paracrine growth factor to a capacity for autonomous growth, dependent on autocrine IL-6 stimulation. Whether such a development also may take place in MM clones in vivo remains to be established.
Blotting, Northern↗
[Choriocarcinoma--an unusual tumor with higher incidence among men].
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Adult↗
[No considerable risks in elective surgery in patients over 90 years of age].
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Aged↗
Interferon gamma abrogates the differentiation block in v-myc-expressing U-937 monoblasts.
Extensive studies suggest a role for the myc protooncogene family in the control of cell proliferation and differentiation in vertebrates. Previously, deregulated expression of exogenous myc genes has been shown to inhibit induced differentiation in Friend erythroleukemia (MEL) cells and in human monoblastic U-937 cells. To examine the nature of the block of phorbol 12-myristate 13-acetate-induced differentiation in v-myc-expressing U-937 cells, we have studied the effect of other inducers utilizing signal pathways distinct from phorbol 12-myristate 13-acetate (i.e., 1 alpha, 25-dihydroxycholecalciferol and retinoic acid). We show that v-myc also inhibits differentiation associated with these inducers. However, the v-myc-associated block of phorbol 12-myristate 13-acetate-, 1 alpha,25-dihydroxycholecalciferol-, and retinoic acid-induced differentiation retinoic acid-induced differentiation can be overcome by adding interferon gamma as a costimulatory factor. Costimulation with interferon gamma restores terminal differentiation, as shown by acquisition of a macrophage phenotype and an irreversible growth arrest in the G0/G1 phase of the cell cycle, but induces only limited differentiation on its own. The differentiation is accomplished without altering the expression or nuclear localization of the v-myc protein. These results argue against the widely held view that down-regulation of myc expression is a general prerequisite for terminal differentiation of hematopoietic cells and suggests that interferon gamma induces a signal(s) that circumvents the v-myc activity.
Blotting, Northern↗