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Biomedical subjects

B Wirleitner

Publications and source records attributed to B Wirleitner.

At least 19 recordsLinked to original sources
PubMed2005

Beer down-regulates activated peripheral blood mononuclear cells in vitro.

Moderate consumption of alcoholic beverages is suggested to reduce cardiovascular risk. Within this context, most attention is drawn to antioxidant ingredients of wine, but also beer was found to be beneficial. Potential effects of three different types of beer including alcohol-free beer were investigated using freshly isolated human peripheral blood mononuclear cells stimulated with the mitogen phytohaemagglutinin in vitro. Neopterin production and tryptophan degradation were monitored in culture supernatants to determine effects of test substances on immunobiochemical pathways induced by interferon-gamma. In a subgroup of experiments also production of interferon-gamma was measured. Compared to unstimulated cells, phytohaemagglutinin increased production of neopterin and also triggered the degradation of tryptophan (all p < 0.01). All types of beer (2-4% dilution) were found to counteract these stimulation-induced effects and significant reduction of neopterin formation and tryptophan degradation was observed (p < 0.01). Data demonstrate that beer reduces production of neopterin and degradation of tryptophan, both these biochemical pathways are induced during cell-mediated immune response. Data suggest that the immunosuppressive capacity of beer may relate to its anti-inflammatory nature.

Anti-Inflammatory Agents↗
PubMed2005

Aspirin down-regulates tryptophan degradation in stimulated human peripheral blood mononuclear cells in vitro.

Acetylsalicylic acid (aspirin) is one of the most widely used drugs worldwide, due mainly to its broad therapeutic spectrum with anti-inflammatory, antipyretic, antithrombotic and analgesic effects. However, the exact mechanisms by which aspirin influences inflammation, pain and immune system activation are only partly understood. Within activation of the cellular immune system, Th1-type cytokine interferon (IFN)-gamma induces enzyme indoleamine-2,3-dioxygenase (IDO) which converts tryptophan to kynurenine. In parallel, IFN-gamma induces enzyme GTP-cyclohydrolase I, which gives rise to neopterin production by activated human macrophages. Similarly, tryptophan degradation and neopterin formation increase during several disease states involving Th1-type immune activation. Using stimulated human peripheral blood mononuclear cells (PBMC), the effect of aspirin on tryptophan degradation and neopterin production was investigated. Stimulation of PBMC with mitogens concanavalin A, phytohaemagglutinin and pokeweed mitogen induced significant tryptophan catabolism as was reflected by a decline in tryptophan levels and a parallel increase in kynurenine concentrations compared with unstimulated cells. In parallel, neopterin production was enhanced. Treatment of stimulated PBMC with increasing doses of 1-5 mM aspirin significantly decreased stimulation-induced tryptophan degradation and neopterin production as well. All the effects of aspirin were dose-dependent. The parallel influence of aspirin on both biochemical pathways implies that there was no direct inhibitory effect of aspirin on IDO; rather, it inhibits production of IFN-gamma in mitogen-treated PBMC. The influence of aspirin on biochemical pathways induced by IFN-gamma may represent an important part of its broad pharmacological effect.

Anti-Infective Agents↗
PubMed2005

Aspirin downregulates homocysteine formation in stimulated human peripheral blood mononuclear cells.

Moderate hyperhomocysteinaemia is established as an independent risk factor for atherosclerosis, thrombosis, stroke and dementia. Hyperhomocysteinaemia is mostly caused by the deficiency of B-vitamins folate and vitamin B12, which are essential cofactors in the remethylation of homocysteine to methionine. Interestingly, moderate hyperhomocysteinaemia is also often observed in chronic diseases, in which also elevated immune activation markers such as neopterin or sTNFR-II are found. In order to simulate immune activation in vitro, human peripheral blood mononuclear cells (PBMC) were stimulated with mitogens. Stimulation significantly increased homocysteine production in comparison with unstimulated PBMC; in parallel also neopterin formation was induced. Homocysteine formation was due to cell proliferation, proliferating T lymphocytes, and also the myelomonocytic cell line U-937 produced homocysteine. Treatment with the anti-inflammatory drug aspirin dose-dependently inhibited homocysteine production and also neopterin formation in human PBMC. Treatment with salicylic acid showed similar effects as aspirin; FACS analysis showed that both compounds inhibited cell proliferation by arresting cells in the G0/G1-phase. In U-937, both compounds also slightly induced apoptosis at 5 mm. Proliferation-induced homocysteine formation and in parallel also monocyte activation can be suppressed effectively by aspirin and salicylic acid in vitro, suggesting that also in vivo aspirin may downregulate not only inflammation but also formation of homocysteine.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

PADMA 28 modulates interferon-gamma-induced tryptophan degradation and neopterin production in human PBMC in vitro.

Tibetan herbal remedy PADMA 28 revealed promising results to support treatment of intermittent claudication, atherosclerosis and chronic hepatitis. The remedy was confirmed to be closely linked with anti- and pro-oxidative properties in vitro. In this study, effect of PADMA 28 was investigated in stimulated and unstimulated human peripheral blood mononuclear cells (PBMC) in vitro. Neopterin production and tryptophan degradation were measured in supernatants of PBMC in the presence or absence of mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A). Stimulation of PBMC induced neopterin formation and tryptophan degradation (p<0.001 compared to unstimulated PBMC), and PADMA 28 inhibited both immunobiochemical effects (p<0.001) in a concentration-dependent manner. Higher concentrations of PADMA 28 were more effective and were able to completely block the pathways induced upon mitogenic stimulation. Data allow to conclude that PADMA 28 is able to inhibit immunobiological effects in stimulated PBMC in vitro. The suppression of neopterin production and tryptophan degradation suggests a specific influence on biochemical pathways induced by Th1-type cytokine interferon-gamma.

Cells, Cultured↗
PubMed2004

In vitro effects of two extracts and two pure alkaloid preparations of Uncaria tomentosa on peripheral blood mononuclear cells.

In the traditional Peruvian medicine, hot aqueous extracts of Uncaria tomentosa have been used for the treatment of a wide range of health problems, particularly digestive complaints and arthritis. Some of the beneficial effects observed in patients suggest an immunomodulatory capacity of Uncaria tomentosa extracts. In this study, the effects of two extracts and two mixtures of tetracyclic and pentacyclic oxindole alkaloids of Uncaria tomentosa were investigated in freshly isolated human peripheral blood mononuclear cells (PBMC) stimulated with the mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A) in vitro. Neopterin production and tryptophan degradation were monitored in culture supernatants to determine the effects of the test substances on immunobiochemical pathways induced by interferon-gamma. Compared to unstimulated cells PHA and Con A increased the production of neopterin and degradation of tryptophan (p < 0.01). HCl and ethanol extracts and mixtures of alkaloids of Uncaria tomentosa inhibited both effects in a dose-dependent manner, the lowest effective concentrations of the extracts were 500 - 1000 microg/mL and of the alkaloid mixtures 100 - 175 microg/mL (p < 0.05 and < 0.01). With the highest concentrations of extracts and mixtures complete suppression of mitogen-induced neopterin production and tryptophan degradation was observed. These data demonstrate that Uncaria tomentosa extracts and mixtures of alkaloids modulate the immunobiochemical pathways induced by interferon-gamma. The findings imply a potential application of the extracts as immunoregulators and would be in line with observations in patients using these extracts.

Adjuvants, Immunologic↗
PubMed2004

Moderate hyperhomocysteinemia and immune activation.

Moderate hyperhomocysteinemia is associated with an increased risk of atherosclerosis, thrombosis and neurodegenerative diseases. Homocysteine accumulation in the blood can be due to many underlying causes, which may interact with each other, e.g. genetic disposition and B-vitamin status. The role of the sulfur-containing amino acid homocysteine in the pathogenesis of diseases remains unclear, even if many studies suggest a causal relationship between homocysteine-mediated processes like oxidative stress, NO-inactivation and endothelial deficiency and atherogenesis. Proposed mechanisms of action of homocysteine are discussed, and the question is addressed, whether effects that are attributed to homocysteine, are not rather the consequence of folate and vitamin B12-deficiency. Deficiency of these B-vitamins in parallel with moderate hyperhomocysteinemia is often found in patients with enhanced activation of the cellular immune system, like Alzheimer's disease, rheumatoid arthritis and also vascular diseases. In patients with these diseases an association between homocysteine metabolism, oxidative stress and immune activation exists. On the one hand proliferation of immunocompetent cells having an enhanced demand for B-vitamins leads to the accumulation of homocysteine. On the other hand macrophages stimulated by TH1-type cytokine interferon-gamma form reactive oxygen species (ROS), which oxidize antioxidants, lipoproteins and oxidation-sensitive B-vitamins. Thereby Th1-type immune response could contribute importantly to the development of hyperhomocysteinemia, and may also be a major determinant of disease progression.

Animals↗
PubMed2003

Potential role of immune system activation-associated production of neopterin derivatives in humans.

Neopterin derivatives are produced by human monocyte-derived macrophages and dendritic cells upon stimulation with interferons. Neopterin concentrations measured in urine or blood reflect activation of cellular immunity and endogenous release of interferon-gamma. This review focuses on the clinical utility of measuring neopterin levels in inflammatory disease and the potential functions of neopterin as a mediator and/or modulator in the course of inflammatory and infectious processes. In vitro-studies revealed that neopterin derivatives exhibit distinct biochemical effects, most likely via interactions with reactive oxygen or nitrogen intermediates, thereby affecting the cellular redox state. Data support the hypothesis that the release of neopterin enhances the cytotoxic potential of activated macrophages and dendritic cells. In vivo, a strong correlation between neopterin levels and the severity, progression, and outcome of infectious and inflammatory diseases was found. The influence of neopterin derivatives on the cellular metabolism may provide an explanation for these clinical observations.

Cell Line↗
PubMed2003

Atorvastatin suppresses interferon-gamma -induced neopterin formation and tryptophan degradation in human peripheral blood mononuclear cells and in monocytic cell lines.

Inhibitors of 3-hydroxy-3methylglutaryl-co-enzyme A (HMG-CoA) reductase, so-called statins, are used in medical practice because of their lipid-lowering effect and to reduce the risk of coronary heart disease. Recent findings indicate that statins also have anti-inflammatory properties and can modulate the immune response. In vitro, we investigated the effect of atorvastatin on the T cell/macrophage system in peripheral blood mononuclear cells (PBMC) and in the human monocytic cell lines THP-1 and MonoMac6. We monitored neopterin production and tryptophan degradation in PBMC after treatment with 10 micro m and 100 micro m atorvastatin in the presence or absence of 100 U/ml IFN-gamma, 10 micro g/ml phytohaemagglutinin (PHA) or 10 micro g/ml concanavalin A (ConA) and in monocytic cell lines THP-1 and MonoMac6 with or without stimulation with 100 U/ml IFN-gamma or 10 ng/ml to 1 micro g/ml lipopolysaccharide (LPS). In stimulated PBMC 100 micro m atorvastatin inhibited neopterin formation and tryptophan degradation completely, whereas 10 micro m atorvastatin was only partially effective. Also in monocytic cell lines THP-1 and MonoMac6, atorvastatin was able to suppress IFN-gamma- and LPS-induced formation of neopterin and degradation of tryptophan. Our data from PBMC agree well with previous investigations that statins inhibit T cell activation within the cellular immune response. In addition we demonstrate that atorvastatin directly inhibits IFN-gamma-mediated pathways in monocytic cells, suggesting that both immunoreactivity of T cells and of monocyte-derived macrophages are down-regulated by this statin.

Atorvastatin↗
PubMed2003

Homocysteine accumulates in supernatants of stimulated human peripheral blood mononuclear cells.

Moderate hyperhomocysteinaemia is associated with atherosclerosis, thrombosis and also with stroke and dementia. Elevated homocysteine concentrations are related to deficiency of folate and also vitamin-B12, as these two vitamins are essential co-factors in the remethylation of homocysteine to methionine. A causal role of homocysteine in the pathogenesis of vascular disease has been discussed over years. Immune activation appears to be involved strongly in atherogenesis as well as in other diseases found to be associated with moderate hyperhomocysteinaemia. To study a possible influence of immune stimulation on homocysteine metabolism, in vitro experiments were performed using peripheral blood mononuclear cells upon stimulation with mitogens concanavalin A, phytohaemagglutinin and pokeweed mitogen. In stimulated cells a dose-dependent increase of homocysteine concentrations was found. When cells were kept in medium supplemented with methionine, homocysteine concentrations increased further, while supplementation with folate had only a slight effect. We conclude that in supernatants of stimulated peripheral blood mononuclear cells homocysteine is accumulating. T cell activation could be involved in the development of moderate hyperhomocysteinaemia.

Cells, Cultured↗
PubMed2003

Immune activation and degradation of tryptophan in coronary heart disease.

BACKGROUND: Inflammation and immune activation appear to be important in the pathogenesis of coronary heart disease (CHD). Cytokine interferon-gamma, which is released during cell-mediated immune responses, induces indoleamine (2,3)-dioxygenase (IDO), an enzyme degrading tryptophan to kynurenine. Therefore, immune stimulation is commonly associated with an increased kynurenine to tryptophan ratio (kyn trp-1) indicative for activated indoleamine (2,3)-dioxygenase and a measurable decline of tryptophan. METHODS: Blood concentrations of kynurenine and free tryptophan and the kynurenine to tryptophan ratio were examined in 35 patients with coronary heart disease verified by coronary angiography and compared with healthy controls. Patients were observed before percutaneous transluminal coronary angioplasty (21 patients: one with artery disease, nine with 2- or 3-artery disease, and five with restenosis). RESULTS AND CONCLUSIONS: Decreased tryptophan concentrations were found in a significant proportion of coronary heart disease patients and coincided with increased kyn trp-1 and also with increased neopterin concentrations, indicating an activated cellular immune response. We conclude that in coronary heart disease immune activation is associated with an increased rate of tryptophan degradation and thereby lowered tryptophan levels. Results may provide a basis for a better understanding of the pathogenesis of mood disturbances and depression in coronary heart disease patients.

Aged↗
PubMed2003

Interferon-gamma-induced conversion of tryptophan: immunologic and neuropsychiatric aspects.

Tryptophan is an essential amino acid and the least abundant constituent of proteins. In parallel it represents a source for two important biochemical pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by the tetrahydrobiopterin-dependent tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides initiated by the enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). Whereas TDO is located in the liver cells, IDO is expressed in a large variety of cells and is inducible by the cytokine interferon-gamma. Therefore, accelerated tryptophan degradation is observed in diseases and disorders concomitant with cellular immune activation, e. g. infectious, autoimmune, and malignant diseases, as well as during pregnancy. According to the cytostatic and antiproliferative properties of tryptophan-depletion on T lymphocytes, activated T-helper type 1 (Th-1) cells may down-regulate immune response via degradation of tryptophan. Especially in states of persistent immune activation availability of free serum tryptophan is diminished and as a consequence of reduced serotonin production, serotonergic functions may as well be affected. Accumulation of neuroactive kynurenine metabolites such as quinolinic acid may contribute to the development of neurologic/psychiatric disorders. Thus, IDO seems to represent a link between the immunological network and neuroendocrine functions with far reaching consequences in regard to the psychological status of patients. These observations provide a basis for the better understanding of mood disorder and related symptoms in chronic diseases.

Animals↗
PubMed2002

Neopterin as a marker for immune system activation.

Increased amounts of neopterin are produced by human monocytes/macrophages upon stimulation with the cytokine interferon-y. Therefore, measurement of neopterin concentrations in body fluids like serum, cerebrospinal fluid or urine provides information about activation of T helper cell 1 derived cellular immune activation. Increased neopterin production is found in infections by viruses including human immunodeficiency virus (HIV), infections by intracellular living bacteria and parasites, autoimmune diseases, malignant tumor diseases and in allograft rejection episodes. But also in neurological and in cardiovascular diseases cellular immune activation indicated by increased neopterin production, is found. Major diagnostic applications of neopterin measurements are, e.g. monitoring of allograft recipients to recognize immunological complications early. Neopterin production provides prognostic information in patients with malignant tumor diseases and in HIV-infected individuals, high levels being associated with poorer survival expectations. Neopterin measurements are also useful to monitor therapy in patients with autoimmune disorders and in individuals with HIV infection. Screening of neopterin concentrations in blood donations allows to detect acute infections in a non-specific way and improves safety of blood transfusions. As high neopterin production is associated with increased production of reactive oxygen species and with low serum concentrations of antioxidants like alpha-tocopherol, neopterin can also be regarded as a marker of reactive oxygen species formed by the activated cellular immune system. Therefore, by neopterin measurements not only the extent of cellular immune activation but also the extent of oxidative stress can be estimated.

Animals↗
PubMed2002

Hyperhomocysteinemia, pteridines and oxidative stress.

Tetrahydrofolate is an essential cofactor for the conversion of homocysteine to methionine, and hyperhomocysteinemia is considered as a risk factor for cardiovascular and cerebrovascular diseases. In subjects with hyperhomocysteinemia usually an inverse relationship exists to folic acid levels, and supplementation with folic acid is able to lower homocysteine concentrations. The pathogenesis of most if not all diseases which are accompanied with moderate hyperhomocysteinemia involves cellular immune activation and therefore in patients very often exists also a positive correlation between homocysteine concentrations and the degree of immune activation which is indicated, e.g. by increased neopterin concentrations. Since neopterin concentrations also serves as an estimate of oxidative stress merging from immune system activation, this association suggests that cellular immune activation and oxidative stress could be involved in the development of hyperhomocysteinemia. Because tetrahydrofolate is very susceptible to oxidation, an increased oxidative degradation of tetrahydrofolates may become relevant under oxidative stress conditions. In this way folate deficiency may develop despite normal dietary intake of the vitamin. In our patients, hyperhomocysteinemia is considered as an indirect consequence of hyperconsumption of antioxidant vitamins during prolonged states of immune activation.

Animals↗
PubMed2001

Influence of cytokines tumor necrosis factor-alpha and interferon-gamma on signaling cascades associated with apoptosis in rat PC12 cells.

During cell-mediated immune response, increased amounts of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) are released. In the present study, we investigated the potential of these two cytokines to mediate apoptosis and to alter signal transduction pathways involved in undifferentiated PC12 cells. To induce apoptosis, the pteridine 7,8-dihydroneopterin (NH2) was used. TNF-alpha alone and TNF-alpha in combination with IFN-gamma led to no alteration in cell viability during 48 h of incubation. TNF-alpha was able to slightly elevate apoptosis compared with cells stimulated with NH2 alone. The combination of TNF-alpha and IFN-gamma almost completely abrogated the rate of apoptosis induced by NH2. Similar degrees of activation of extracellular protein kinase were found after the addition of cytokines or cytokines in combination with NH2. Stress-activated protein kinase (SAPK) was not activated by the cytokines alone, whereas adding the cytokine TNF-alpha to NH2-stimulated cells resulted in activation of SAPK after 15 min.

Animals↗
PubMed2001

Induction of apoptosis by 7,8-dihydroneopterin: involvement of radical formation.

Interferon-gamma is a cytokine released in large amounts during cell-mediated immune response. It induces the expression of proinflammatory cytokines and enhances macrophage capacity to secrete reactive oxygen intermediates and the pteridines neopterin and 7,8-dihydroneopterin. To assay the role of these pteridines in the immune system several studies were performed. Thereby, 7,8-dihydroneopterin was found to induce apoptosis in T lymphocytes. In this study we report that caspases are involved in 7,8-dihydroneopterin-mediated apoptosis in Jurkat T cells. In connection with this result we found that 7,8-dihydroneopterin can increase Fas ligand expression detected in Western blot analysis and promoter reporter assays. Antioxidants potently reduced the effect of 7,8-dihydroneopterin on Fas ligand promoter activation suggesting an involvement of oxidative stress. In further investigations, ESR-measurements were performed to evaluate the role of 7,8-dihydroneopterin in the formation of radicals. We found that the pteridine in combination with the spin trap DMPO induces the production of DMPO-OH spin adducts. This reaction was sensitive to the presence of chelated metal ions and could completely be blocked by the addition of superoxide dismutase. These data suggest that 7,8-dihydroneopterin in aqueous solution leads to the formation of .OH radicals via generation of superoxide anion. We hypothesize that an overproduction of radicals caused by high levels of 7,8-dihydroneopterin is likely to be responsible for the pro-apoptotic effects observed in cell cultures and possibly contributes to the pathogenesis of diseases involving immune activation and elevated concentrations of neopterin-derivatives.

Apoptosis↗
PubMed2001

Neopterin production in SCID mice injected with human peripheral blood mononuclear cells.

Intraperitoneal transfer of peripheral blood mononuclear cells (PBMC) from human EBV+ donors into severe combined immunodeficiency (SCID) mice is a suitable model for studying some aspects of lymphomagenesis and immune activation. Neopterin is a soluble immune marker which was found to be a useful indicator for immune activation processes in humans, e.g. to monitor immunological complications in allograft recipients or to predict prognosis in HIV-infected individuals. In contrast, this pteridine compound is normally synthesized in murine organism in only very low amounts. The measurement of neopterin concentrations in serum and urine should be feasible in SCID mice reconstituted with human PBMC. In this study, we examined the usability of this experimental model for monitoring human T cell activation by neopterin measurements. The production of neopterin by SCID mice after injection of freshly isolated human PBMC, purified B or T cells and cultured Epstein-Barr virus (EBV)+ lymphoblastoid cells (LCL) was determined. It was found that neopterin can be detected early after injecting SCID mice with PBMC, whereas injection of purified human T or B cells did not result in neopterin production. Highest neopterin levels were detected in mice treated with LCL cells when developing lymphoma. We discuss the possible sources of neopterin along this process and its usefulness in this model.

Animals↗
PubMed2001

Aqueous extracts of Crinum latifolium (L.) and Camellia sinensis show immunomodulatory properties in human peripheral blood mononuclear cells.

In Vietnamese and Chinese traditional medicine, hot aqueous extract of Crinum latifolium is used because of its antitumor activity. The genus Crinum is thought to possess antiviral and immunostimulative properties. Green and black tea derived from Camellia sinensis have similar qualities. A growing body of evidence suggests that moderate consumption of green and black tea may protect, e.g., against several forms of cancer, cardiovascular diseases, and bacterial infections. In this study, the immunomodulatory property of C. latifolium (L.) extracts should further be investigated and compared to those of black and green tea. Human peripheral mononuclear cells were cultured in the presence of tea extracts with or without mitogens or interferon-gamma. The effect of plant extracts on cultured cells was assayed by neopterin production, a sensitive marker reflecting the activation of cell-mediated immunity. Our experiments showed that extracts of C. latifolium (L.) slightly enhance neopterin production in unstimulated peripheral mononuclear cells, whereas an effective reduction of neopterin formation in cells stimulated with concanavalin A (Con A), phytohemagglutinin (PHA), or interferon-gamma (IFN-gamma) was observed. Green and black tea extracts displayed similar immunomodulatory properties in our in vitro system, whereas C. latifolium (L.) extracts seemed to be more effective in reducing neopterin formation in stimulated cells.

Adjuvants, Immunologic↗