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Biomedical subjects

U Andersson

Publications and source records attributed to U Andersson.

At least 109 records · Page 6Linked to original sources
PubMed1993

Studies on the link between HMG-CoA reductase and cholesterol 7 alpha-hydroxylase in lymph-fistula rats: evidence for both transcriptional and post-transcriptional mechanisms for down-regulation of the two enzymes by bile acids.

The mechanism of down-regulation of hepatic HMG-CoA reductase and cholesterol 7 alpha-hydroxylase by cholic acid (CA) and chenodeoxycholic acid (CDCA) was investigated in rats with a lymph fistula. In accordance with the contention that bile acids are able to down-regulate HMG-CoA reductase by a mechanism independent of their effect on cholesterol absorption, inclusion of the above bile acids in diet (1%, wt/wt) reduced the HMG-CoA reductase specific activity by about 80%. The levels of mRNA were reduced by about 50% and the transcription rate (nuclear run-on) by 27% and 35%, respectively. Thus, HMG-CoA reductase appears to be regulated at both a transcriptional and a post-transcriptional level by bile acids. The cholesterol 7 alpha-hydroxylase activity as well as the corresponding mRNA levels were both reduced by about 50% by the same treatments. The transcription rate of the cholesterol 7 alpha-hydroxylase was not significantly affected by the treatment with CDCA, whereas the CA treatment reduced the transcription rate by about 24%. It is evident that bile acids regulate these two enzymes by different mechanisms in this model, in spite of the fact that the levels of mRNA were affected to about the same degree. The most obvious difference was the marked suppression of HMG-CoA reductase activity by cholic acid with relatively modest effects on transcription rate and level of mRNA. The latter finding is interesting in view of recent reports that dietary cholesterol also seems to down-regulate HMG-CoA reductase predominantly by a post-transcriptional mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Lipopolysaccharide induces human interleukin-1 receptor antagonist and interleukin-1 production in the same cell.

A new member of the interleukin-1 (IL-1) family has recently been described. Human IL-1 receptor antagonist (IL-1ra) is structurally related to IL-1 alpha and IL-1 beta but binds to IL-1 receptors on various target cells without demonstrable agonist activity. Understanding the mechanisms of regulation of IL-1ra production may clarify the biology of this unique cytokine as well as elucidate its possible role as a natural anti-inflammatory protein. The effects of lipopolysaccharide (LPS) on IL-1 alpha, IL-1 beta and IL-1ra production was studied at a single-cell level by use of cytokine-specific antibodies and indirect immunofluorescence technique. The peak synthesis of IL-1ra and IL-1 alpha/beta occurred in peripheral blood monocytes obtained from healthy blood donors within 4 and 6 h of cell stimulation, respectively. By double-staining procedure all IL-1ra-positive cells were also IL-1 alpha and/or beta positive. Thus, endotoxin induced simultaneous synthesis of the IL-1 gene family in the same cells. Only monocytes contributed to the production of IL-1 alpha, beta and IL-1ra during the 96 h of cell culture. The maximum number of IL-1ra-producing monocytes was 48 +/- 16% as compared to peak production of IL-1 alpha and beta which occurred in 75 +/- 9% and 80 +/- 12% (p < 0.001), respectively, of all peripheral blood monocytes. The incidence of IL-1 alpha- and beta-containing cells was not only significantly higher but also occurred for a longer time period, 72 h as compared to 24 h for IL-1ra localized in the Golgi organelle. However, IL-1ra-containing cells with a diffuse cytoplasmic appearance were also evident (20%-30%) at a later stage, 12 to 72 h after stimulation. Blocking IL-1 surface receptors by addition of exogenous recombinant IL-1 beta before stimulation could not inhibit the diffuse cytosolic localization. This indicates that the "late" staining pattern did not reflect IL-1ra being secreted and internalized after binding to extracellular receptors. Thus, perhaps IL-1ra modulates IL-1 effector mechanisms by receptor interactions both inside and outside the cell.

Adult↗
PubMed1992

Endotoxin and Staphylococcus aureus enterotoxin A induce different patterns of cytokines.

The effects of Staphylococcus aureus enterotoxin A (SEA) and lipopolysaccharide (LPS) in cytokine production were assessed at the single cell level in cells obtained from healthy blood donors. Cytokine production was studied with UV-microscopy of fixed and permeabilized cells stained with cytokine specific monoclonal antibodies. The cytokines evaluated included tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha, IL-1 beta, IL-6, IL-8, IL-10, IL-2, IL-4, interferon (IFN)-gamma and TNF-beta. LPS exhibited marked production of IL-1 alpha, IL-1 beta, TNF-alpha, IL-6 and IL-8. After LPS stimulation IL-1 alpha, IL-1 beta, TNF-alpha and IL-8 were the dominating products, all peaking at or before 4 hours after cell stimulation. In addition, IL-10 production was evident after 12 hours of cell stimulation. The T-lymphocyte-derived cytokines TNF-beta, IL-2, IFN-gamma and IL-4 were never detected in the cultures. All cytokine production, except IL-8, was downregulated at 96 hours. In contrast, peak production of IL-1 alpha, IL-1 beta and IL-8, which were the dominant products, occurred after 12 hours in the SEA-stimulated cultures. Further, a significant T-lymphocyte production of TNF-beta, TNF-alpha, IFN-gamma and IL-2 was found with peak production 12-48 hours after initiation. Only low amounts of IL-6 were evident. The two types of cytokine pattern and kinetics found may correspond to the different clinical conditions after invasive Gram-negative Escherichia coli vs Gram-positive Staphylococcus aureus infections in humans, with a much more rapid onset of disease after E. coli infections.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytokines↗
PubMed1992

Borrelia arthritis in Swedish children: clinical manifestations in 10 children.

Since 1986, serology against Borrelia burgdorferi has been performed on patients with arthritis admitted to the Division of Pediatric Rheumatology, S:t Göran's Hospital, Stockholm. We studied, retrospectively, the period 1986-88. Among 300 children with arthritis, 10 had positive titers against B. B. burgdorferi. Other causes of arthritis were excluded. The onset of Borrelia arthritis was throughout the year. Only 3 of the 10 children remembered an actual tick bite. No other manifestations of Lyme borreliosis were present simultaneously. The typical clinical picture was a relapsing unilateral arthritis of the knee.

Adolescent↗
PubMed1992

Effects of FK506 and cyclosporin A on cytokine production studied in vitro at a single-cell level.

Mononuclear cells obtained from human blood were mitogen or antigen activated in vitro in the presence or absence of FK506 or cyclosporin A (CsA). Cytokine production was studied at a single-cell level by ultraviolet (UV) microscopy of fixed permeabilized cells using cytokine-specific monoclonal antibodies (mAb). Phenotypic characterization of the monokine-producing cells was achieved by two-colour immunofluorescent staining. Cytokine production after antigen activation with Staphylococcus aureus enterotoxin A (SEA) was significantly reduced. FK506 or CsA inhibited SEA-induced tumour necrosis factor-alpha (TNF-alpha) production both in monocytes (P less than 0.01) and in lymphocytes (P less than 0.001), at a drug concentration of 1-25 ng/ml for FK506 and 100-500 ng/ml for CsA. Lymphocyte synthesis of interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and TNF-beta after SEA activation was also significantly reduced by either of the drugs. In contrast, endotoxin-induced monokine production (TNF-alpha and IL-6) after lipopolysaccharide (LPS) stimulation was unaffected by FK506 or CsA even when added in concentrations as high as 1000 ng/ml. When the cells were stimulated by phorbol ester (phorbol 12-myristate 13-acetate, PMA) plus calcium ionophore (ionomycin), FK506 and CsA inhibited, in a dose-dependent manner, the production of IL-2, IL-4, IL-5, IFN-gamma and TNF-alpha. The 50% inhibitory concentration (IC50) for FK506 or CsA on the cellular synthesis of the various cytokines varied between 0.6 and 1.0 ng/ml and 20 and 60 ng/ml, respectively. Further stimulation by addition of anti-CD28 mAb to the cultures resulted in an augmented IL-2 and IFN-gamma production which was resistant to both FK506 and CsA. This report delineates extensive similarities between the two drugs in mechanisms of immunosuppression by blockade of identical interleukin production. Depending on the mode of cell activation the two drugs inhibited not only cytokine production in lymphocytes but also antigen-induced monokine (TNF-alpha) production in macrophages, although the optimal immunomodulatory effect of FK506 was achieved at a concentration approximately 50-fold lower than that of CsA.

Antigens, CD↗
PubMed1991

Hypercytokinemia in familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is a frequently missed and almost uniformly fatal childhood disorder. It is characterized by fever, hepatosplenomegaly, cytopenia, coagulopathy, and hypertriglyceridemia. The pathogenesis of FHL is not known but the above clinical and laboratory findings are compatible with reported in vitro and in vivo effects of several inflammatory cytokines. We measured circulating interferon-gamma (IFN-gamma), tumor necrosis factor/cachectin (TNF), and interleukin-6 (IL-6) in nine children with FHL. During active disease, elevated IFN-gamma was detected in seven of seven children, TNF in six of six, and IL-6 in two of six children studied. Thus, important inflammatory cytokines are augmented in active FHL and may contribute to the pathogenesis of the disease. Soluble CD8 was also increased in seven of seven children, which suggests a pathophysiologic importance of cytotoxic T lymphocytes. Because FHL appears to be associated with a systemic hypercytokinemia, our results also indicate that studies of FHL may contribute to the understanding of cytokine effects in vivo. Moreover, FHL is a hereditary disorder, suggesting that the hypercytokinemia is caused by a genetic defect in cytokine regulation.

CD8 Antigens↗
PubMed1991

On the mechanism of stimulation of cholesterol 7 alpha-hydroxylase by dietary cholesterol.

In agreement with previous work, treatment of rats with cholesterol, 2% in diet, stimulated the cholesterol 7 alpha-hydroxylase activity more than 2-fold. With less than 1% in diet, no significant effect was obtained. Intravenous infusion of cholesterol-enriched Intralipid had no stimulatory effect. In accordance with some recent work by other groups, it was shown that the stimulation of the cholesterol 7 alpha-hydroxylase by dietary cholesterol was associated with elevated levels of mRNA corresponding to the enzyme. Most of the stimulation of the activity induced by dietary cholesterol could not be prevented by lymphatic drainage. Feeding lymph fistulated rats with 2% cholesterol in diet stimulated the cholesterol 7 alpha-hydroxylase almost 2-fold, indicating that under the conditions employed, a major part of the cholesterol-induced stimulation of the activity was due to factor(s) unrelated to the flux of cholesterol from the intestine to the liver. There was a good correlation between the amount of cholesterol excreted in faeces and the activity of the cholesterol 7 alpha-hydroxylase. The half-life of intraperitoneally administered labelled cholic acid was significantly shorter in rats treated with 2% cholesterol in diet (t1/2 = 1.2 +/- 0.1 days) than in control rats (t1/2 = 1.9 +/- 0.18 days). A notable finding was that the weight of faeces was considerably higher in rats fed cholesterol than in the controls. It is hypothesized that a high dietary load of cholesterol causes increased binding of bile acids in the intestine and increased loss of bile acids in faeces. This leads to a reduced suppression of the cholesterol 7 alpha-hydroxylase by the bile acids. The results support the contention that the flux of bile acids rather than the flux of cholesterol from the intestine is the major direct regulator of bile acid biosynthesis.

Animals↗
PubMed1991

Pharmacokinetics and effects on prolactin of remoxipride in patients with tardive dyskinesia.

The pharmacokinetics of remoxipride, a new selective dopamine-D2 receptor antagonist with antipsychotic action, was evaluated in eight elderly psychiatric patients with tardive dyskinesia (TD). The daily oral doses of remoxipride were gradually increased from 50 mg per day to 200 mg t.i.d. over 2 weeks. The pharmacokinetics following the initial 50 mg dose (day 1) and the last 200 mg dose (day 15) of the drug were compared in serial samples. Plasma prolactin concentrations were assessed at the same time points. The area under the total plasma concentration versus time curves (AUC) of remoxipride increased proportionally with dose from day 1 to 15. The mean "dose corrected" AUC values for the total concentrations were 96.8 at day 1 (4 X 24.2, 50 mg single oral dose) and 92.2 mumol.h/l at day 15 (200 mg). The unbound fraction of remoxipride calculated on AUC was slightly higher on day 15 (20%) than on day 1 (15%) (P less than 0.05), indicating slightly concentration-dependent protein binding of the drug. The mean elimination half-life of total remoxipride was slightly longer on day 15 than day 1 (7.5 versus 5.3 h, P less than 0.01) The corresponding half-lives for the unbound concentrations were 6.4 and 3.9 h, respectively (P less than 0.01). The pharmacokinetics of remoxipride is similar in these TD patients and in non-TD patients in previous studies. Following repeated administration of remoxipride, tolerance to the prolactin-releasing action of remoxipride is observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1990

Production of TNF-alpha and TNF-beta by staphylococcal enterotoxin A activated human T cells.

Staphylococcal enterotoxin at concentrations of less than 1 pg/ml induces significant TNF activity in human peripheral blood T cells and monocytes. Maximal TNF activity is routinely detected after 48 to 72 h of culture. IL-2 and IL-4 were both growth promoting for human T cells but only IL-2 could efficiently induce TNF production. The production of TNF-alpha and TNF-beta differed greatly in kinetics. An early intracytoplasmatic production of TNF-alpha after 6 h was detected in both monocytes and T cells whereas a late production of TNF-beta (lymphotoxin) after 48 h, occurred in the T cell population. Induction of TNF-alpha and TNF-beta production by Staphylococcal enterotoxin requires the presence of both monocytes and T cells. The CD4+45R- but not CD4+45R+ and CD8+ cells supported TNF-alpha production in monocytes. The main lytic component from Staphylococcal enterotoxin-activated mononuclear cells is TNF-beta. CD4+ and CD8+ T cells produced about equal amounts of biologically active TNF into the culture supernatants but a fourfold higher frequency of TNF-beta producing cells was demonstrated among CD4+ vs CD8+ cells. The CD4+45R- T cell subset was an efficient producer of TNF-beta and IFN-gamma whereas the CD4+45R+ T cell subset produced significant amounts of TNF-beta but only marginal amounts of IFN-gamma.

Antigen-Presenting Cells↗
PubMed1990

Simultaneous production of interleukin 2, interleukin 4 and interferon-gamma by activated human blood lymphocytes.

The production of interleukin 2 (IL 2), IL 4 and interferon-gamma (IFN-gamma) by in vitro activated unselected human blood mononuclear cells was studied at a single-cell level. Individual lymphokine-synthesizing cells were identified by intracellular immunofluorescent staining using cytokine-specific monoclonal or polyclonal antibodies. Cultures from adult blood donors revealed a biphasic kinetic production pattern for IL 2 and IFN-gamma with peaks occurring 4-6 and 24-30 h after initiation of the cultures. Approximately 20%-40% of the lymphocytes produced IL 2 and IFN-gamma. In contrast, only 1%-3% of the lymphocytes synthesized IL 4 with maximal frequency after 6 h of culture. CD4+ as well as CD8+ T cells contributed to the synthesis of all three lymphokines studied. CD4+CD45R- T cells were the major producers of IL 2 and IL 4, while CD8+CD45R- T cells were the most common phenotype of IFN-gamma-synthesizing cells. By performing two-color immunofluorescence studies we observed that among IL 4-producing cells every second one made simultaneously IL 2 and every fourth one made IFN-gamma. Mononuclear cells from umbilical cord blood could be stimulated to make IL 2 to the same extent as cells from adult blood donors. No IL 4 production and a strikingly reduced frequency of IFN-gamma producers were noted in cell cultures from neonates. IL 2, IL 4 and IFN-gamma accumulated in the Golgi system, which resulted in a characteristic morphology of the staining, eliminating problems with evaluation of background signals.

Adult↗
PubMed1990

Striatal binding of 11C-NMSP studied with positron emission tomography in patients with persistent tardive dyskinesia: no evidence for altered dopamine D2 receptor binding.

Dopamine D2 receptor binding characteristics were studied by positron emission tomography (PET) using N-11C-methyl spiperone as receptor ligand in patients on longterm treatment with neuroleptic drugs and in control subjects. Eight of the patients had symptoms of tardive dyskinesia whereas three patients did not have any symptoms. Control subjects comprised 5 healthy volunteers and 7 patients with pituitary tumors. All patients had been free of neuroleptic drugs for at least 4 weeks. The time dependent regional radioactivity in the striatum was measured and the receptor binding rate, k3, proportional to receptor number, Bmax and association rate for the receptor was calculated in relation to the cerebellum. The lack in difference in k3 values between TD patients, neuroleptic treated patients without TD and control subjects throws doubt on the hypothesis that changes in striatal D2 dopamine receptor number or binding affinity is an etiological mechanism for persistent TD.

Aged↗
PubMed1990

Production by activated human T cells of interleukin 4 but not interferon-gamma is associated with elevated levels of serum antibodies to activating malaria antigens.

T cells play a crucial role in antibody-mediated and antibody-independent immunity against Plasmodium falciparum malaria. Therefore, a vaccine immunogen should include parasite-derived B- and T-cell epitopes capable of giving rise to protective responses in both systems. The P. falciparum antigen Pf155/ring-infected erythrocyte surface antigen (RESA), a vaccine candidate, contains immunodominant T- and B-cell epitopes located in the central (5') and C-terminal (3') invariant repeat regions of the molecule. To relate Pf155/RESA-peptide-specific responses of T cells to function, T cells from P. falciparum immune donors were activated with peptides corresponding to these immunodominant regions. Activation was measured as induction of interferon-gamma secretion, T-cell proliferation (DNA synthesis), or transcription and translation of interleukin 4 (IL-4) mRNA. Peptides from both regions were shown to induce interferon-gamma, IL-4, proliferation, or any combination. In individual donors, there was no correlation between these different activities. Rather, they were negatively correlated, demonstrating the importance of examining multiple parameters of T-cell activation when estimating the proportion of individuals responding to a given epitope. However, IL-4 mRNA and intracellular IL-4 could be induced in T cells of donors who had elevated concentrations of serum antibodies to the same peptide that was used for T-cell activation. These results suggest that a causal relationship exists between the activation of IL-4-producing T-cell subsets and production of the anti-Pf155/RESA-specific antibodies in individuals in which immunity has been induced by natural infection. This finding has implications that should be considered for the selection of immunogens to be included in a future P. falciparum subunit vaccine and for vaccine development in general.

Adult↗