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Biomedical subjects

L Rink

Publications and source records attributed to L Rink.

At least 55 records · Page 3Linked to original sources
PubMed1996

Induction of a proinflammatory cytokine network by Mycoplasma arthritidis-derived superantigen (MAS).

Mycoplasma arthritidis is an arthritogenic organism for rodents, producing a superantigen (MAS). It has been postulated that mycoplasmas or superantigens thereof might play a role in human rheumatoid arthritis. Since M. arthritidis fulfills both, the present study was performed to investigate MAS-specific cytokine induction. Human or murine leukocytes were stimulated with MAS, staphylococcal enterotoxin E (SEE), or lipopolysaccharide (LPS). Cytokines were measured by ELISA, Bioassay, and RT-PCR. The response to MAS in humans was individually restricted, in contrast to the response to SEE or LPS. Furthermore, MAS showed the same capacity for inducing proinflammatory cytokines as interleukin (IL)-1 IL-6, and IL-8 as SEE and LPS. However, MAS showed a significantly decreased capacity to induce the anti-inflammatory cytokine IL-10 and IL-1RA. In mice, the reactivity to MAS was strictly MHC-II restricted, in contrast to that of SEE or LPS. The individual response to MAS in humans might be explained by the difference of the HLA-DR haplotype because H-2-differing mouse strains showed the same discrepancies. MAS induced an overproduction of proinflammatory cytokines, when its ability to induce proinflammatory and anti-inflammatory cytokines was compared with those of SEE and LPS. The individual response may explain an MHC linkage, and the failure to induce anti-inflammatory cytokines may be the reason for a chronic disease in contrast to acute inflammation.

Animals↗
PubMed1996

Major depressive disorder is associated with elevated monocyte counts.

One of the most consistently reported findings in depression has been leucocytosis. In 33 in-patients with major depressive disorder, we assessed white blood cell count (WBC) and lymphocyte subsets four times over a period of 6 weeks. The control group consisted of 44 healthy subjects. Shortly after admission, we detected significant increases in the numbers of leucocytes, granulocytes, platelets and monocytes in the depressed patients. Patients who recovered well during hospitalization showed a decrease in monocyte counts, whereas those with slower clinical improvement had significantly higher monocyte counts than the control group. This longitudinal study demonstrates that monocytes may play a role in the acute phase of depression and could provide an explanation for immunological dysfunction in depressive states.

Adolescent↗
PubMed1996

Recent progress in the tumor necrosis factor-alpha field.

Tumor necrosis factor (TNF is used synonymously with TNF-alpha) is a pleiotropic cytokine. The effects of TNF were first described in the last century, but the soluble factor was discovered in 1975. Now TNF is one of the most important cytokines investigated by scientists from different fields. This short review briefly summarizes the state of the art and adds the news of the last 2 years. The progress in the field of TNF is focussed on gene organization and transcription, gene polymorphism, biochemistry of TNF, TNF receptors and the biological role of TNF in autoimmune diseases, infectious diseases, transplantation, cancer and TNF functions on endothelial cells.

Animals↗
PubMed1996

Interferon-gamma plays a key role in the human mixed lymphocyte culture.

Measurement of cytokines in the mixed lymphocyte culture (MLC) is thought to be a new and relevant parameter for bone marrow transplantation (BMT). Our experiments showed that IFN-gamma plays a central role in the cytokine network following alloantigenic recognition. IFN-gamma itself is induced by IL-2 since anti-IL-2 strongly reduced the secretion of IFN-gamma. As anti-IFN-gamma also diminished the response of IL-2 and sIL-2R, a feedback mechanism between these two cytokines is assumed. Addition of rIFN-gamma to the MLC augmented the release of sCD8 molecules, whereas sCD4 molecules were reduced, indicating that IFN-gamma led to T cell differentiation instead of IL-2 dependent proliferation. In the MLC, a feedback mechanism between TNF-alpha and IFN-gamma exists, since anti-TNF-gamma reduced the secretion of IFN-gamma and anti-IFN-gamma inhibited the release of TNF-alpha. Therefore, IFN-gamma plays a critical role in monocyte activation, T cell differentiation, and IL-2-induced cell growth. We conclude that measurement of IFN-gamma might be a new and more sensitive parameter for BMT than the established proliferation assay, since IFN-gamma directly quantifies T cell activation.

Antigens, CD↗
PubMed1995

Influence of serum on zinc, toxic shock syndrome toxin-1, and lipopolysaccharide-induced production of IFN-gamma and IL-1 beta by human mononuclear cells.

Measurement of cytokine secretion in vitro is usually performed in culture medium supplemented with human serum. We compared the secretion of interferon-gamma and interleukin-1 beta as a parameter for lymphocyte and monocyte activation in RPMI 1640 medium supplemented with fetal calf or autologous serum in serum-free medium and protein-free medium. Four different stimulatory mechanisms were tested: phytohemagglutinin, toxic shock syndrome toxin-1 (TSST-1), lipopolysaccharide (LPS), and zinc ions. We found that the optimal stimulatory zinc concentration depended on the total protein content of the medium, whereas the monokine levels were dependent on the concentration of transport proteins such as transferrin. Monokine induction by LPS or TSST-1 were each influenced by the protein and serum composition in a specific manner. Our results show that the differing mechanisms of cytokine induction are influenced by the medium and serum composition in a diverse but specific manner. Serum- or protein-free medium are especially suitable after superantigen challenge when LPS activity needs to be ruled out or after activation by agents with only a weak stimulatory capacity.

Bacterial Toxins↗
PubMed1995

Divergent effects of zinc on different bacterial pathogenic agents.

Zinc is essential for immunologic function; therefore, it has been postulated that elevated serum levels of zinc might lead to improved immune responses. However, it is not known whether or how serum zinc levels contribute to a clinically relevant mechanism of immunologic activation. In our studies with human peripheral blood mononuclear cells and whole blood, the zinc level selectively enhanced the biologic activity of endotoxin. The combination of nonstimulatory doses of lipopolysaccharide (LPS) and nonstimulatory concentrations of zinc led to the secretion of large amounts of interleukin (IL)-1 beta. In contrast, zinc levels specifically down-regulated monocyte activation caused by some superantigens, staphylococcal enterotoxin A and E and Mycoplasma arthritidis--derived superantigen, but not toxic shock syndrome toxin-1. This demonstrates that zinc levels control IL-1 beta secretion after both LPS and superantigen challenge within a clinically relevant range of concentrations. Our data suggest that the indications and contraindications for clinical zinc supplementation should be reconsidered.

Drug Synergism↗
PubMed1995

Cytokine production and serum proteins in depression.

One, as yet unemployed, approach to investigating immunology in depression is the assessment of the cytokine production by leucocytes, which would allow the determination of immune response under standardized conditions. Thus we measured the production of mitogen-induced cytokines (IL-1 beta, IL-2, IL-6, IL-10, interferon-gamma) and sIL-2R in a whole blood assay, and serum protein levels such as C-reactive protein (CRP), haptoglobin (Hp) and alpha 2-macroglobulin (alpha 2 M) in a longitudinal 6-week study in an attempt to assess leucocyte function during and after acute clinical stage of depression in 39 patients. Shortly after admission to hospital we found higher levels of all measured cytokines in the patients. Serum protein levels were significantly higher in the patients than in controls, and decreased over the study period. Whereas slightly elevated monokine levels in patients tended to reach control values, lymphokines showed a significant decrease over the 6 weeks as compared to baseline. These results suggest that the increase in immune activity seen at the beginning of the study may be followed by a suppressed cell-mediated immune function.

Acute-Phase Proteins↗
PubMed1995

Zinc regulates cytokine induction by superantigens and lipopolysaccharide.

Zinc is known to be greatly involved in the regulation of immune functions. Pharmacological zinc supplementation, leading to serum zinc concentrations of more than 0.025 mM, has often been suggested to improve immune responses. However, the exact influence of elevated zinc level on immune functions has not yet been investigated. We found that zinc level selectively enhances cytokine induction by lipopolysaccharide (LPS) in a concentration-dependent fashion: as little as 0.0125 mM supplemental zinc led to nearly 50% elevated interleukin-1 beta (IL-1 beta) levels both in polymorphonuclear cells (PBMC) and whole-blood cultures. The secretion of interferon-gamma (IFN-gamma) could be increased more than 10-fold by 0.1 mM zinc. This could not be observed during stimulation with phytohaemagglutin (PHA). In contrast, zinc levels concentration-dependently down-regulated monocyte activation caused by the superantigens, staphylococcal enterotoxins A and E (SEA, SEE, more than 90% down-regulation by 0.1 mM zinc), the Mycoplasma arthritidis-derived superantigen (MAS), but not toxic shock syndrome toxin-1 (TSST-1), while T-cell response remained unaffected. This was not the result of chemical degradation of the superantigens. We assume that zinc concentration regulates interactions between SEA, SEE and MAS, but not TSST-1 and their major histocompatibility complex (MHC) class II-binding sites. Our data demonstrate that zinc levels control the secretion of IFN-gamma and monokines after both LPS and superantigen challenge within a clinically relevant range of concentrations. This reveals new perspectives and indications for zinc supplementation and also indicates potential risks of therapeutic application of zinc.

Bacterial Toxins↗
PubMed1994

Cytokine interactions in human mixed lymphocyte culture.

Human PBMC of healthy blood donors were used to investigate the interaction of cytokines in human MLC. Two-way MLC was performed because irradiation did not influence the cytokine release. We found different kinetic patterns for IL-2, IFN-gamma, and sIL-2R. Production of IFN-gamma was dependent on IL-2 release because anti-IL-2 addition resulted in more than 90% reduced IFN-gamma levels. Treatment with rIL-2 altered IFN-gamma kinetics, but not the total amount of IFN-gamma. Addition of anti-IFN-gamma led to decreased production of IL-2 and sIL-2R. A down-regulation of IL-2 and sIL-2R could also be observed after treatment with rIFN-gamma. No production of IL-4 and IL-10 was detected in MLC (detection limit 5 pg/ml). This could not be explained by IFN-gamma antagonism because IL-4 and IL-10 were not detectable even after addition of anti-IFN-gamma. Testing the TH1-TH2 cell antagonism, the addition of rIL-4 and rIL-10 resulted in IFN-gamma suppression depending on the timing of exposition. Treatment with rIL-10 inhibited IL-2 and sIL-2R release. We found no production of IL-1 alpha and IL-1 beta in MLC, whereas IL-6 and TNF-alpha release could be detected. Surprisingly, release of IL-6 and TNF-alpha could be blocked completely by addition of anti-IFN-gamma. This suggests that the release of IL-6 and TNF-alpha in MLC is dependent on IFN-gamma produced by T cells. In summary, TH1 cytokines play a central role in MLC regulation, whereas TH2 cytokines appear to be of little importance.

Cytokines↗
PubMed1994

Modulation of Mycoplasma arthritidis-derived superantigen-induced cytokine gene expression by dexamethasone and interleukin-4.

Activation of human monocytes or monocytic cell lines with all known stimuli coordinately induces the gene expression of various cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and the IL-1 receptor antagonist (IL-1Ra). In contrast, superantigens induce TNF-alpha and IL-1 beta but fail to affect IL-1Ra gene expression, suggesting that activation of monocytes via major histocompatibility complex class II is distinct from other signal transduction pathways. In the present study, we analyzed the regulation of the Mycoplasma arthritidis-derived superantigen (MAM)-induced IL-1 beta and TNF-alpha gene expression by studying the effects of two different anti-inflammatory agents: dexamethasone (DEX) and the T-cell-derived cytokine IL-4. Both agents contributed to the downregulation of MAM-induced IL-1 beta and TNF-alpha gene expression. They accelerated the normal decline of the gene expression of both MAM-induced cytokines by decreasing the stability of mRNAs via the induction or enhanced synthesis of one or more regulatory proteins. In addition, IL-4, but not DEX, induced a strong and rapid expression of IL-1Ra mRNA in MAM-stimulated and unstimulated THP-1 cells in a de novo protein synthesis-independent manner. The capacity of IL-4 to induce IL-1Ra gene expression reinforces its anti-inflammatory activity. This study illustrates some of the mechanisms by which MAM-induced proinflammatory monokine gene expression can be downregulated by IL-4 and DEX.

Cycloheximide↗
PubMed1994

Differential induction of tumor necrosis factor alpha in murine and human leukocytes by Mycoplasma arthritidis-derived superantigen.

Mycoplasma arthritidis-derived superantigen (MAS) is exclusively produced by M. arthritidis, which is the only known mycoplasma to produce a superantigen. As a superantigen, MAS shows properties similar to those of the staphylococcal enterotoxins and related substances, such as binding to major histocompatibility complex (MHC) class II and V beta-specific stimulation of T cells. In this series of experiments, we demonstrate some differences between MAS and other superantigens. MAS induced the production of tumor necrosis factor alpha (TNF-alpha) mRNA in human as well as in murine leukocytes. However, only in murine leukocytes was the mRNA adequately translated into the protein. In human peripheral blood mononuclear cells, we found only small amounts of TNF, whereas in murine spleen cells we detected levels more than three times higher. The proliferative response to MAS has been shown to be restricted to I-E alpha in the murine MHC. Furthermore, TNF was induced in I-E alpha+ bone marrow-derived macrophages by MAS. In these cells, MAS rapidly induced very high levels of TNF and the amounts of mRNA detected correlated to the amount of protein produced. In comparison with other superantigens, including the staphylococcal enterotoxins, toxic shock syndrome toxin 1, and exfoliative toxin A, the failure of MAS to induce TNF-alpha in human peripheral blood mononuclear cells is specific for MAS and not common to all superantigens. The direct activation of bone marrow-derived macrophages also seems to be specific for MAS. These data suggest that the induction of TNF-alpha by MAS is dependent on the strength of binding to the MHC class II molecule.

Animals↗
PubMed1994

Mycoplasma arthritidis-derived superantigen induces proinflammatory monokine gene expression in the THP-1 human monocytic cell line.

Soluble factors produced by Mycoplasma arthritidis play an important role in the pathology of arthritis in rodents, which closely resembles human rheumatoid arthritis. At least one of the products of these microorganisms, M. arthritidis-T cell mitogen (MAM), has biological activities in common with superantigens. These superantigens activate T cells in a V beta-restricted fashion, and this response is strictly dependent on the presence of major histocompatibility complex (MHC) class II-positive cells. In the present study, we have examined the ability of MAM to induce proinflammatory monokine (interleukin 1 beta [IL-1 beta] and tumor necrosis factor alpha [TNF-alpha]) gene expression in the THP-1 monocytic cell line. Treatment of these cells (which express a very low level of HLA-DR molecules) with gamma interferon (INF-gamma) induced HLA-DR, -DQ, and -DP molecules and enabled them to respond to MAM in a dose-dependent manner, resulting in an increase in the level of steady-state mRNA for IL-1 beta and TNF-alpha. Stimulation of the U937 monocytic cell line (MHC class II-negative even after INF-gamma treatment) with MAM did not induce either IL-1 beta or TNF-alpha transcription. Moreover, MAM adsorption on Raji (MHC class II-positive) cells resulted in the loss of its cytokine-inducing activity to induce monokine gene expression. These findings demonstrate clearly that MAM induces monokine gene expression following interaction with MHC class II molecules. Pretreatment of INF-gamma-treated THP-1 cells with the transcription inhibitor actinomycin D prevented the induction of monokine mRNA, whereas cycloheximide superinduced mRNA after stimulation with MAM. Finally, our results, obtained with protein tyrosine kinase inhibitors and antiphosphotyrosine Western blotting (immunoblotting), indicate that protein tyrosine kinase is involved in MAM-induced IL-1 beta and TNF-alpha gene expression in the THP-1 monocytic cell line. The capacity of MAM to induce proinflammatory cytokine transcription in monocytes via MHC class II molecules can be one pathway of MAM contribution to autoimmune diseases.

Antigens↗
PubMed1994

Identification of HLA-DRB1 and HLA-DQB1 identical individuals by a cytokine-based mixed lymphocyte culture.

Cytokine determination in MLC is under discussion as providing more sensitive and specific information regarding host-graft compatibility, and is therefore suggested to represent a new method for transplantation medicine. Little is known, however, about the stimulatory influence of HLA class II antigens and minor lymphocyte-stimulating antigens (Mls). Our results demonstrate that cytokine determination in MLC is suitable to detect identical alleles of HLA-DRB1 and HLA-DQB1. Among more than 100 random MLC experiments, we observed one cytokine pattern similar to the cytokine release detected in a control MLC of HLA-identical siblings, which showed marginal or no secretion of IL-2, sIL-2R, IFN-gamma, TNF-alpha, and IL-6. HLA-typing of these two nonreactive individuals elevated identical HLA-DRB1 and HLA-DQB1 regions, while they differed in the HLA-DP locus. This suggests that HLA-DP has no stimulatory influence on cytokine release. Further investigation of the stimulatory capacity of HLA-DR and DQ showed that HLA-DR is more effective in inducing IFN-gamma release than HLA-DQ. To evaluate the stimulatory influence of human Mls, i.e., human endogenous retroviruses (HERV), we analyzed HERV sequences of nonreactive individuals. Both individuals showed identical HERV patterns. A third individual, who had shown distinct cytokine release in MLC with both nonreactive individuals, differed in the HERV fragments. In conclusion, cytokine determination in MLC is a new method of evaluating the biological relevance of stimulatory antigens after allogeneic stimulation detecting all individual diversities in one experiment.

Alleles↗
PubMed1994

Thalassemia major in Connecticut: a 20-year study of changing age distribution and survival.

There has been a near doubling of the mean age (10.7 to 19.0 years) of Yale-New Haven Hospital patients with transfusion-dependent homozygous beta thalassemia between 1973 and 1994. This change is, in part, a result of improved transfusion procedures and effective chelation therapy with deferoxamine mesylate. A concomitant trend has been a decrease in the number of births of new cases resulting in fewer thalassemia major patients less than 10 years of age in 1985 and 1994 compared to a decade earlier. Identification of individuals at risk of having children with thalassemia major by extensive screening for heterozygous thalassemia and the availability of prenatal diagnosis may have contributed to this change. Thalassemia major has become a disease of adolescents and young adults. The increasing age has resulted in "new" issues in thalassemia major patients such as sexuality and marriage as well as economic problems involving health-care insurance and employment.

Adolescent↗
PubMed1994

Induction of cytokines by zinc ions in human peripheral blood mononuclear cells and separated monocytes.

Zinc plays an important role in the maintenance of immune functions. The immunological mechanisms triggered by zinc, however, are still poorly understood. In our experiments Zn2+ ions, added as ZnSO4, stimulated PBMC to produce IFN-gamma, IL-1 beta, IL-6, TNF-alpha, and sIL-2R in a concentration-dependent manner. CuSO4 and CaCl2 as cation and anion controls had no effect. The optimal concentration of zinc was 0.5 mM for monokine induction and 0.25 mM for induction of IFN-gamma and sIL-2R. The highest IL-1 beta and IL-6 levels were found on day 2 and maximum TNF-alpha after 16 h. IFN-gamma and sIL-2R production were optimum after 6 and 7 days, respectively. Monokines could be induced in autologous serum as well as in fetal calf serum and serum-free medium. Enriched monocytes and the human monocyte cell line Mono Mac 6 also released IL-1 beta after zinc challenge. Anti-IL-6 reduced IFN-gamma secretion whereas anti-IL-1 beta inhibited it. These data suggest that zinc acts primarily on monocytes by inducing monokine secretion and that T-cell activation represents a secondary effect in the cytokine cascade.

Cell Line↗
PubMed1992

In situ hybridization of the mRNA for interferon-gamma, interferon-alpha E, interferon-beta, interleukin-1 beta and interleukin-6 and characterization of infiltrating cells in thyroid tissues.

Cytokine mRNA production in the thyroid tissues of patients with various thyroid diseases was analysed by in situ hybridization. In addition, infiltrating leukocytes were characterized by immunohistologic studies using the alkaline phosphatase anti-alkaline phosphatase (APAAP) staining technique. The following clinical material was investigated: two cases of Graves' disease, one with high and the other with a low amount of infiltrating leukocytes as well as two cases of non-toxic goitre also showing considerable quantities of infiltrating cells. The hybridization was performed on tissue sections with antisense probes for interferon-gamma (IFN-gamma), IFN-alpha E, IFN-beta, interleukin-6 (IL-6) and IL-1 beta. A small number of individual cells were found to express high levels of mRNA for IFN-gamma, IL-1 beta and measurable amounts of IL-6 throughout the tissue sections. However, IFN-alpha E or IFN-beta were not detected. Cytokine expressing cells were noted in the tissue of one patient with Graves' disease and in two cases with non-toxic goitre. In these samples a high amount of infiltrating leukocytes (CD45+) was detected, especially CD3+, CD8+, CD4+ and CD45RA+ T cells, in addition to B cells and macrophages. In one case an unusually large amount of T cell receptor gamma/delta+ (TcR gamma/delta+) cells was found. However, one sample of thyroid tissue derived from a patient with Graves' disease was poorly infiltrated and showed few cells expressing cytokines. In conclusion, using thyroid tissue as an example, our data suggest that the application of in situ hybridization with antisense RNA permits the study of cytokine production in tissues of both autoimmune and non-autoimmune origin.

Adult↗