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M Hurme

Publications and source records attributed to M Hurme.

At least 73 records · Page 4Linked to original sources
PubMed1999

Polymorphisms of the interleukin-1 gene complex in schizophrenia.

Activation of the inflammatory response system has been related to the pathophysiology of schizophrenia by several recent studies. Schizophrenic patients have varied levels of proinflammatory cytokines, such as interleukin (IL)-1, -6, and tumor necrosis factor (TNF)alpha in their peripheral blood or cerebrospinal fluid. These cytokines can modify the metabolism of neurotransmitters, influence neural development, and IL-1 has been implicated in acute, and, on the other hand, chronic neurodegeneration. They could therefore be of primary pathogenic importance, either in the acute disease or during those stages of brain development which possibly influence the sensitivity of a person to schizophrenia in later life. The cytokine regulation of brain development and its possible neuroimmune involvement in the pathogenesis of schizophrenia has been raised. One indication of the pathogenic role of IL-1 in schizophrenia would be a demonstration of the difference between schizophrenic patients and healthy controls at the gene level. Therefore we analyzed the polymorphism of the IL-1 gene complex in 50 schizophrenic patients and in 400 healthy blood donors. The following allelisms were analyzed: IL-1beta gene: base exchange polymorphisms at the positions -511 (relative to the transcriptional start site); IL-1alpha gene: base exchange polymorphism at the position -889; IL-1 receptor antagonist (IL-1RA) gene: variable numbers of 86-base pair tandem repeats in intron 2. The frequencies of the IL-1beta (-511) allele 1, IL-1alpha (-889) allele 2, and IL-1RA allele 1 were somewhat, but not significantly, higher in the schizophrenic patients as compared to the controls. These alleles are known to be located on the same haplotype. The number of carriers of this haplotype was significantly higher in the schizophrenia patients (17/50 vs 81/400) than in the controls (P=0.026, chi2). The frequencies of this haplotype were 0.38 and 0.27, respectively (P=0.0266, chi2). The number of homozygotes of this haplotype was significantly higher in the schizophrenia patients (P=0.0006, chi2). These data suggest that the cytokine aberrations in schizophrenia are, at least partly, genetically determined.

Adult↗
PubMed1999

Normal T-helper 1/T-helper 2 balance in peripheral blood of coeliac disease patients.

Activated T cells, with their secretion of cytokines, probably play an important role in the pathogenesis of mucosal lesions in coeliac disease (COD) and the prominence of a T-helper (Th)1-type cytokine pattern has been reported. As the process of immunological activation in the jejunal mucosa in active CoD has been shown to also cause some differences in peripheral blood lymphocyte populations, we sought to establish any changes in the Th 1/Th2 balance in peripheral blood of patients, at different stages of CoD, relative to healthy individuals. Twenty-two CoD patients and 10 healthy controls were included in the study. The Th1/Th2 balance was examined both in resting cells and after polyclonal stimulation using two different methods: intracytoplasmic cytokine contents were measured using an intracellular staining method and three-colour flow cytometry and cytokine contents of cell culture supernatants were measured using traditional enzyme-linked immunosorbent assays (ELISAs). Interferon-gamma (IFN-gamma)-producing cells (Thl) were as prominent in untreated CoD patients and treated CoD patients as in healthy controls, while cells fitting a Th2 or ThO-type cytokine pattern were few in all groups. In ELISA assays, Th1 type (IFN-gamma or interleukin (IL)-2) cytokines were again prominent in all study groups but no statistically significant differences were found in IFN-gamma, IL-4 or IL-2 levels among the three groups. These results suggest that the increased shift towards a Th1 response is mainly restricted to the actual site of inflammation and that circulating T cells do not show a similar response, presumably because activated cells in peripheral blood are too few. Further research on cytokine profiles measuring T-cell activation in CoD should be focused on the actual tissue of inflammation.

Adolescent↗
PubMed1999

Polymorphism of the interleukin-10 gene is associated with susceptibility to Epstein-Barr virus infection.

There are indications that the cytokine interleukin (IL)-10 has a regulatory role in Epstein-Barr virus (EBV)-induced infections. Because the human IL-10 gene demonstrates polymorphism resulting in interindividual differences in cytokine production, the frequencies of the alleles defined by the base exchange polymorphism at the position -1082 (allele 1=G, allele 2=A) were analyzed in EBV-seronegative adults, seropositive adults, and in patients hospitalized because of a severe EBV infection. The frequencies of allele 1 were 0.80, 0.46, and 0.29, respectively. Because this allele is associated with a high IL-10-producing capability, these data suggest that high IL-10 levels protect against EBV infection and, conversely, that low IL-10-producing capability makes individuals more susceptible to a severe EBV infection.

Adult↗
PubMed1999

Increased in vitro production of interleukin 6 in response to trimethoprim among persons with trimethoprim induced systemic adverse reactions.

OBJECTIVE: Trimethoprim occasionally triggers a systemic adverse reaction including fever, malaise, head and backache, and even overt meningeal irritation, particularly in women with an autoimmune rheumatic disease. To study the unknown pathogenesis of the reaction we measured the effect of trimethoprim upon the cytokine [interleukin (IL) 2, 6, 10, and tumor necrosis factor-alpha] production of trimethoprim reactive and tolerant persons' peripheral blood mononuclear cells in vitro. METHODS: Peripheral blood mononuclear cells from 12 women reactive to trimethoprim (3 with primary Sjögren's syndrome, 3 with systemic lupus erythematosus, 1 with systemic scleroderma, 5 with no rheumatic disease) were cultured in the presence of trimethoprim, and the cytokine production was measured. Eleven women who tolerated trimethoprim (6 with Sjögren's syndrome and 5 with no rheumatic disease) served as controls. RESULTS: Therapeutic trimethoprim concentration induced in the mononuclear cells of the trimethoprim reactive patients significantly higher IL-6 production [mean +/- SD (median), 2034+/-2965 (572) pg/ml] versus cells of the trimethoprim tolerant subjects [954+/-2552 (89) pg/ml; p = 0.036]. No significant differences in the production of other cytokines were detected. CONCLUSION: Trimethoprim induces IL-6 production in the peripheral blood mononuclear cells of trimethoprim reactive persons. We suggest that IL-6 production is the probable trigger leading to the clinical reaction.

Adult↗
PubMed1998

Pre-exposure to oxidative stress decreases the nuclear factor-kappa B-dependent transcription in T lymphocytes.

Reactive oxygen species (ROS) are used as signaling molecules in T cell activation. One of the main targets of ROS is the transcription factor nuclear factor-kappa B (NF-kappa B). NF-kappa B-dependent transcription is inhibited by antioxidants, and the activation is induced or potentiated by ROS. However, chronic oxidative stress is known to reduce the activation of T cells and NF-kappa B. To analyze these phenomena in more detail, we have exposed Jurkat T cells in vitro to oxidative stress (H2O2) at various times before or simultaneously with signals known to activate NF-kappa B (phorbol dibutyrate (PDBu) and TNF). Simultaneously applied H2O2 strongly potentiated the PDBu- or TNF-induced transcriptional activity of NF-kappa B. In contrast to this, H2O2 given 3 to 20 h before the activating signal reduced NF-kappa B-dependent transcriptional activity. This was not due to the oxidation-induced modification of NF-kappa B; cytoplasmic NF-kappa B was able to bind to DNA after dissociation from I kappa B alpha by detergent treatment. H2O2 pre-exposure effectively inhibited the PDBu- or TNF-induced phosphorylation and degradation of I kappa B alpha, but H2O2 given simultaneously with PDBu or TNF enhanced the degradation. Oxidative stress was also followed by a strongly decreased ability to form intracellular ROS. Taken together, these data indicate that I kappa B alpha phosphorylation is the target of action of ROS, and as the ROS-forming capacity is weaker after chronic oxidative stress, I kappa B alpha is not effectively phosphorylated and degraded, thus leading to decreased NF-kappa B-dependent transcription.

DNA-Binding Proteins↗
PubMed1998

IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes.

The genes in the IL-1 complex code for three proteins, IL-1alpha, IL-1beta and the IL-1 receptor antagonist (IL-1 Ra). The severity of a given infection is influenced by the balance between the levels of IL-1beta, the major extracellular agonist, and that of IL-1 Ra. In healthy individuals, IL-1 Ra is readily detectable in plasma but IL-1beta levels are usually undetectable. As there are polymorphisms in both of these genes, we have now analyzed whether there are allelic associations between these loci and whether these would have an influence on plasma IL-1 Ra levels. In 200 healthy blood donors, the mean plasma IL-1 Ra concentration was 681 pg/ ml. The IL-1Ra allele 2 (IL1RN*2) had a clear influence on IL-1Ra levels: its carriers had higher levels than the non-carriers (745 ng/ml vs. 627 pg/ml, p < 0.05, t-test). As marker alleles for IL-1beta we used two biallelic base-exchange polymorphisms (at positions -511 and +3953 relative to the transcriptional start site). The more rare allele of IL-1beta -511 (allele 2) was significantly associated with the presence of IL-1 Ra allele 2, but in the case of the IL-1beta +3953, the more rare allele (allele 2) was less frequent in the carriers of the IL-1 Ra allele 2. These IL-1beta allelisms did not have a direct influence on plasma IL-1Ra levels, but the enhancing effect of IL-1 Ra allele 2 on IL-1 Ra plasma levels required the presence of the IL-1beta -511 allele 2 or absence of the IL-1beta +3953 allele 2. Taken together, these results indicate that the IL-1beta gene participates in the regulation of IL-1 Ra production in vivo and that the alleles of IL-1beta and IL-1 Ra which demonstrate this cooperative effect are often associated.

Adolescent↗
PubMed1998

CD28-mediated activation in CD45RA+ and CD45RO+ T cells: enhanced levels of reactive oxygen intermediates and c-Rel nuclear translocation in CD45RA+ cells.

We have analyzed the effect of complete T cell activation (anti-CD3 plus anti-CD28) on the activation of NF-kappaB in CD45RA+ (naive) and CD45RO+ (memory/effector) T cells. Long exposure (24 h) induced stronger NF-kappaB DNA binding in CD45RA+ cells than in CD45RO+ cells. Analysis of the nuclear c-Rel protein indicated that after anti-CD3+anti-CD28 stimulation the level of c-Rel was higher in CD45RA+ cells. Analysis of the cytoplasmic inhibitor IkappaBalpha indicated that anti-CD3+anti-CD28 stimulation induced a long-lasting degradation in CD45RA+ cells but in CD45RO+ cells the degradation process was more rapid. Because the CD28 costimulus is known to induce the production of reactive oxygen intermediates (ROIs), the intracellular ROI levels in CD45RA+ and CD45RO+ cells were compared by flow cytometry. ROIs were produced in both cell types, but more strongly in CD45RA+ cells. The data presented in this study further emphasize the differences between CD45RA+ and CD45RO+ T lymphocytes in ROI-dependent signaling pathways.

Adult↗
PubMed1998

Elevated levels of interleukin-6 may occur in cerebrospinal fluid from patients with recent epileptic seizures.

Experimental animal studies suggest the involvement of cytokines in epilepsy. We measured increased concentrations of interleukin-6 in four out of 15 cerebrospinal fluid samples from unmedicated patients with newly developed tonic-clonic seizures; plasma levels were also increased but to a lesser extent. Although the significance of cytokine production in relation to epileptic seizures is not known, it might be important for neuronal survival.

Adolescent↗
PubMed1998

Diminished production of interleukin-6 in chronic lymphocytic leukaemia (B-CLL) cells from patients at advanced stages of disease. Tampere CLL Group.

The production of the cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in B-CLL cells from 24 patients at different stages of chronic lymphocytic B-cell leukaemia (B-CLL) was investigated in vitro. In the majority of these cases, low spontaneous IL-6 production was measured. Mitogenic stimulation with phorbol 12-myristate 13-acetate (PMA) or PMA plus interleukin-2 (IL-2) resulted in a tremendous increase in TNF-alpha and IL-6 production in cells representing early stage (Binet A) disease. In contrast, very little, if any, production took place in cells from patients with advanced stage (Binet C) B-CLL. The results from stage B patients were intermediate. The most remarkable difference was recorded in PMA-stimulated (1 ng/ml) IL-6 production. In stimulated 72 h cultures, IL-6 concentrations were 1280 +/- 1080 pg/ml for Binet A (n = 11), 757 +/- 597 pg/ml for Binet B (n = 8) and 46.0 +/- 84.0 pg/ml for Binet C (n = 5). The differences in IL-6 production between stage C v B and stage C v A were both statistically significant (P=0.025). Similar effects, but to a lesser extent, were observed in TNF-alpha production. These results suggest that the varying capacity to produce IL-6 and TNF-alpha may play a role in B-CLL progression and in clinical manifestations of the disease.

Aged↗
PubMed1998

Low CD3+CD28-induced interleukin-2 production correlates with decreased reactive oxygen intermediate formation in neonatal T cells.

The capacity of neonatal T cells to secrete interleukin-2 (IL-2) has been reported to be variable. We analysed IL-2 production in purified neonatal and adult T cells using polyclonal activator phorbol ester + calcium ionophore (PDBu + iono) or receptor-mediated anti-CD3/anti-CD3+ anti-CD28 stimulation. PDBu + iono induced equally high IL-2 levels in both groups and, when stimulated with plate-bound anti-CD3 monoclonal antibody (mAb), the IL-2 secretion by neonatal cells was undetectable and adult cells produced low amounts of IL-2 (mean 331 +/- 86 pg/ml). The addition of anti-CD28 mAb to anti-CD3-stimulated cells markedly increased IL-2 production in both cell types, but levels of IL-2 in neonatal T cells remained clearly lower than those of adult T cells (respective mean values: 385 +/- 109 pg/ml and 4494 +/- 1199 pg/ml). As NF-kappa B is a critical transcription factor in the control of IL-2 expression, we next analysed its nuclear translocation in neonatal and adult T cells using the electrophoretic mobility shift assay and, because induction of reactive oxygen intermediates (ROI) is required for the activation of NF-kappa B, we also analysed levels of intracellular ROI in these cells using the ROI-reactive fluorochrome DCFH-DA and flow cytometry. In neonatal T cells NF-kappa B activation and ROI formation after anti-CD3 stimulation were low compared with adult T cells and, although addition of anti-CD28 mAb increased induction of NF-kappa B and ROI formation, levels similar to those of adults were not achieved. After PDBu + iono stimulation, the cells showed similar ROI formation and IL-2 secretion. Our results suggest that reduced IL-2 production by neonatal T cells is specific for anti-CD3 and anti-CD3+ anti-CD28-mediated stimulation and that these activators cannot effectively activate the ROI-NF-kappa B signalling pathway in neonatal T cells.

Adult↗
PubMed1998

Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro.

The genes of the interleukin-1 (IL-1) complex code for three proteins: IL-1alpha, IL-1beta and the IL-1 receptor antagonist (IL-1RA). Each of these genes is polymorphic and there is increasing evidence that certain alleles are associated with increased susceptibility to a given disease of inflammatory nature. In the IL-1beta gene there are two base-exchange polymorphisms in positions -511 and +3953, and IL-1RA gene has a penta-allelic polymorphic site in intron 2 containing variable numbers of an 86-bp tandem repeat sequence. As the IL-1beta/IL-1RA ratio may be critical in the regulation of inflammation, we examined whether there are allelic associations between these loci (thus suggesting co-ordinate regulation) and whether these have an effect on the in vitro production of IL-1beta. We found that the IL-1RA allele 2 (IL1RN*2) is associated with the presence of allele 2 of the IL-1beta gene (position -511) and with the absence of allele 2 of the IL-1beta gene (position +3953). Mononuclear cells from carriers of allele 2 (position -511) and non-carriers of allele 2 (position +3953) had a slight, but non-significant, elevated capacity to produce IL-1beta in vitro. However, IL-1RA allele 2 strongly increased in vitro production of IL-1beta, regardless of the presence or absence of these alleles. Taken together, these data suggest that the known allelisms in the IL-1beta gene are not major regulators of the in vitro IL-1beta production, but the IL-1RA allele 2 (or an unknown allele strongly associated with it) has a decisive role.

Alleles↗
PubMed1998

Polymorphism of the IL-1 gene complex in Epstein-Barr virus seronegative and seropositive adult blood donors.

Epstein-Barr virus (EBV) seronegativity is rare in adults. To examine whether genetic differences would explain this, we studied the genetic polymorphisms of the genes of the interleukin-1 (IL-1) complex in seronegative adults. These cytokines (i.e. IL-1alpha, IL-1beta and IL-1 receptor antagonist, IL-1RA) regulate, in several ways, the inflammatory reactions of the body. In each of these genes there are polymorphic sites and the various alleles differ in their frequency in several diseases of inflammatory nature. In 400 healthy blood donors (from 18 to 60 years of age) there were 20 (5%) seronegative persons. The frequency of allele 2 of the IL-1beta gene (base exchange polymorphism at position -511 from the transcriptional start site) was decreased in the seronegative patients (0.20 versus 0.42 in the seropositive patients, P < 0.05, chi2-test). Moreover, the frequency of allele 2 of the IL-1RA (polymorphism defined by variable numbers of 86-bp repeats in intron 2) was slightly, but not significantly, decreased in the seronegative patients. Alleles of these two loci are known to be associated, but in the seronegative patients this association was abnormal: 11 out of 20 (55%) were of the IL-1RA-2 negative/IL-1beta-2 negative type, while of the seropositive patients, 25% were of this type (P < 0.01, chi2-test). These data suggest that immunological differences, depending on cytokine gene polymorphisms, regulate the resistance to EBV infection.

Adolescent↗
PubMed1998

Resistance to human cytomegalovirus infection may be influenced by genetic polymorphisms of the tumour necrosis factor-alpha and interleukin-1 receptor antagonist genes.

To examine whether there are genetic differences between cytomegalovirus (CMV)-seronegative and CMV-seropositive adults, the polymorphisms of cytokine genes were analysed in a cohort of 400 adult blood donors. The genes and polymorphic sites studied were the tumour necrosis factor-alpha (TNF-alpha) gene (base exchange polymorphism at position -308; alleles TNF1 and TNF2) and the interleukin-1 receptor antagonist (IL-1RA) gene (variable numbers of 86-bp repeats in intron 2). In this material there were 85 (21%) seronegative persons. The frequencies of the TNF2 and the IL-IRA allele 2 (IL1RN*2) carriers were slightly increased in the seronegative compared with the seropositive samples (39% vs. 29%, and 55% vs. 47%, respectively). The presence of both of these alleles together was significantly (p < 0.05, chi2-test) more frequent in the seronegative population. These data suggest that the alleles of these cytokines, which are known to be associated with a strong inflammatory reaction, may have a protective role against CMV infection.

Adult↗
PubMed1998

Optimized mitogen stimulation induces proliferation of neoplastic B cells in chronic lymphocytic leukemia: significance for cytogenetic analysis.The Tampere Chronic Lympocytic Leukemia group.

We tested the effects of interleukin-2 (IL-2), human recombinant tumor necrosis factor alpha (TNF-alpha), Staphylococcus aureus Cowan I (SAC), TPA, and their combinations, using a standard thymidine incorporation assay, in order to identify an optimal mitogen combination (OMC) for 24 consecutive patients with B-cell chronic lymphocytic leukemia (B-CLL). The combination that induced the highest thymidine incorporation was chosen as the OMC for each patient. Among 14 mitogen combinations tested, there were six different OMCs, of which the most frequent was TNF-alpha + IL-2. It was the OMC in 9 of 24 cases. The other OMCs were TNF-alpha + TPA1 (5/24), SAC + IL-2 (5/24), TPA1 + IL-2 (3/24), TPA10 + IL-2 (1/24), and TNF-alpha + TPA10 + IL-1 (1/24). The mitogenic power of the selected OMC in each case was then evaluated both by the combination of immunophenotyping and molecular cytogenetic techniques known as MAC (Morphology, Antibody, Chromosomes) and standard chromosome analysis. After OMC stimulation, the levels of DNA synthesis and B-cell proliferation (mitotic index) were, on average, 10-fold higher than those observed after standard TPA stimulation (P < 0. 0001). The proportion of mitotic B cells exceeded the proportion of mitotic T cells in 70.1% of the cases after OMC stimulation. After TPA stimulation, 7.7% +/- 2.5% of all mitoses were B-cell mitoses, whereas after OMC stimulation this proportion rose to 57.9% +/- 5.3%. The frequency of clonal chromosomal aberrations increased from 46% after TPA stimulation to 79% after OMC stimulation. The clonal aberrations del(6q), del(11q), and/or del(13q) were observed in 26%, 32%, and 42% of the patients with the respective clonal chromosomal aberrations, whereas the corresponding frequencies after TPA stimulation were only 4%, 21%, and 17%. When the lineage involvement of cells with clonal chromosomal aberrations from three patients was analyzed, the aberrations were found to be restricted to B cells only, and in one patient to a minor subset of B cells. The results demonstrate that an individually chosen OMC induces a high rate of proliferation in neoplastic B cells. We found deletions in 6q, 11q, and 13q at higher frequencies than reported previously, most probably as a result of an improved mitogenic response. The identification of an optimal mitogen stimulation for each patient, prior to chromosome analysis, can well be expected to reduce the rate of false-normal results in the future. This is essential for accurate evaluation of the prognostic significance of chromosomal aberrations in B-CLL.

Aged↗
PubMed1998

Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases.

Cytokines are proteins that regulate immune and inflammatory reactions as well as haematopoiesis. This group of molecules is very heterogeneous including, for example, several interleukins (IL), tumour necrosis factors (TNF) and colony-stimulating factors (CSF). The cytokines participating in the regulation of the inflammatory response are IL-1, IL-1 receptor antagonist (IL-1RA), IL-6, IL-10 and TNF. Functionally they can be divided into proinflammatory (IL-1, IL-6, TNF) and anti-inflammatory (IL-1RA, IL-10) molecules. There is evidence that the inflammatory response must be finely tuned: too strong a response causes the various adverse effects associated with infectious and autoimmune diseases, while a weak inflammatory response attenuates the subsequent immune response. It has now been demonstrated that several of the cytokine genes are polymorphic. In this review we describe the polymorphisms of the two inflammatory cytokines, IL-1 and IL-10, and their significance in various diseases of autoimmune or inflammatory nature.

Autoimmune Diseases↗