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S Endres

Publications and source records attributed to S Endres.

At least 37 records · Page 2Linked to original sources
PubMed2001

Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production.

Interleukin (IL)-18, initially described as interferon (IFN)-gamma-inducing factor, is expressed in the inflamed mucosa of patients with Crohn's disease. To investigate the role of IL-18 in intestinal inflammation, the effect of neutralizing antimurine IL-18 antiserum in dextran sulfate sodium (DSS)-induced colitis in BALB/c and C57BL/6 mice was examined. During a dose response of DSS, levels of colonic IL-18 increased parallel with clinical worsening. With the use of confocal laser microscopy, the increased IL-18 was localized to the intestinal epithelial layer. Anti-IL-18 treatment resulted in a dose-dependent reduction of the severity of colitis in both BALB/c and C57BL/6 mice. Colon shortening following DSS-induced colitis was partially prevented in the treatment groups. In the colon tissue homogenates, IFN-gamma concentrations were lower in the anti-IL-18-treated DSS-fed mice compared with untreated DSS-fed mice. This suppressive effect of anti-IL-18 administered in vivo was also observed on spontaneous tumor necrosis factor-alpha, IL-18, and IFN-gamma production from ex vivo colon organ cultures. The stimulation of lamina propria mononuclear cells by IL-18 and IL-12 resulted in a synergistic increase in IFN-gamma synthesis. These findings suggest that IL-18 is a pivotal mediator in experimental colitis.

Animals↗
PubMed2001

Adenosine kinase inhibitor GP515 improves experimental colitis in mice.

Adenosine is a potent anti-inflammatory mediator. Through elevation of endogenous adenosine concentrations the adenosine kinase inhibitor GP515 might serve to down-regulate local inflammatory responses. In the present study we investigated the effect of systemic GP515 in the nonacute model of dextran sulfate sodium (DSS)-induced colitis. The clinical score, colon length, histologic score, colon cytokine production, and spleen weight from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving GP515 treatment were determined and compared with untreated control mice. Splenocytes were analyzed for phenotype, interferon-gamma (IFNgamma) production, and CD69 expression. First, GP515 treatment resulted in a significant improvement of clinical score (weight loss, stool consistency, and bleeding) and of histologic score. Second, colon shortening, an indirect parameter for the degree of inflammation, was decreased, consistent with a decreased IFNgamma concentration in the colonic tissue. Third, spleen weight was reduced in GP515-treated DSS mice. And fourth, IFNgamma synthesis and CD69 expression, as a marker for early cell activation, of ex vivo-stimulated splenocytes were suppressed in the GP515-treated DSS mice. These studies show that GP515 is effective in the therapy of DSS-induced colitis. One potential mechanism of action is the suppression of IFNgamma synthesis and CD69 expression. Adenosine kinase inhibition forms a pharmacologic target that should be further investigated for chronic inflammatory bowel disease.

Adenosine Kinase↗
PubMed2001

CpG DNA increases primary malignant B cell expression of costimulatory molecules and target antigens.

Multiple factors, including expression of costimulatory molecules, antigen-presenting molecules, and target antigens, likely impact the efficacy of antibody therapy and other approaches to the immunotherapy of B cell malignancy. Unmethylated CpG-dinucleotides in select base contexts ("CpG motifs") that resemble sequences found in bacterial DNA are potent immunostimulatory agents capable of inducing a complex immune response, including a strong B cell stimulus. We examined the effect of a potent human CpG oligonucleotide (CpG ODN 2006) on different types of primary human malignant B cells and reactive follicular hyperplasia. CpG oligodeoxynucleotide (CpG ODN), but not control (non-CpG ODN), increased the expression of costimulatory molecules (CD40, CD80, CD86, CD54) on malignant B cells without altering the phenotype of B cells obtained from reactive follicular hyperplasia. CpG ODN also enhanced expression of class I and class II MHC in most samples. CD20 expression was increased in response to CpG ODN, most notably in B-CLL and marginal zone lymphoma. An inverse correlation was found between baseline expression of CD20 and CD40 and their expression after exposure to CpG ODN, thus the most significant increase in expression of these molecules was found in those samples that had the lowest baseline levels. In conclusion, CpG ODN can lead to increasing expression of molecules involved in costimulation, antigen presentation, and as targets for antibody-based therapy and deserve further evaluation as potential immunotherapeutic agents for B cell malignancy.

Antigen Presentation↗
PubMed2000

Enhanced dendritic cell maturation by TNF-alpha or cytidine-phosphate-guanosine DNA drives T cell activation in vitro and therapeutic anti-tumor immune responses in vivo.

Dendritic cells (DC) manipulated ex vivo can induce tumor immunity in experimental murine tumor models. To improve DC-based tumor vaccination, we studied whether DC maturation affects the T cell-activating potential in vitro and the induction of tumor immunity in vivo. Maturation of murine bone marrow-derived DC was induced by GM-CSF plus IL-4 alone or by further addition of TNF-alpha or a cytidine-phosphate-guanosine (CpG)-containing oligonucleotide (ODN-1826), which mimics the immunostimulatory effect of bacterial DNA. Flow cytometric analysis of costimulatory molecules and MHC class II showed that DC maturation was stimulated most by ODN-1826, whereas TNF-alpha had an intermediate effect. The extent of maturation correlated with the secretion of IL-12 and the induction of alloreactive T cell proliferation. In BALB/c mice, s.c. injection of colon carcinoma cells resulted in rapidly growing tumors. In this model, CpG-ODN-stimulated DC cocultured with irradiated tumor cells also induced prophylactic protection most effectively and were therapeutically effective when administered 3 days after tumor challenge. Thus, CpG-ODN-enhanced DC maturation may represent an efficient means to improve clinical tumor vaccination.

Adjuvants, Immunologic↗
PubMed2000

Extracellular ATP and TNF-alpha synergize in the activation and maturation of human dendritic cells.

Extracellular ATP mediates numerous biological activities by interacting with plasma membrane P2 purinergic receptors. Recently, P2 receptors have been described on dendritic cells (DC), but their functional role remains unclear. Proposed functions include improved Ag presentation, cytokine production, chemotaxis, and induction of apoptosis. We investigated the effects of ATP and of other P2 receptor agonists on endocytosis, phenotype, IL-12 secretion, and T cell stimulatory capacity of human monocyte-derived DC. We found that in the presence of extracellular ATP, DC transiently increase their endocytotic activity. Subsequently, DC up-regulate CD86, CD54, and MHC-II; secrete IL-12; and exhibit an improved stimulatory capacity for allogeneic T cells. These effects were more pronounced when chemically modified ATP derivatives with agonistic activity on P2 receptors, which are resistent to degradation by ectonucleotidases, were applied. Furthermore, ATP and TNF-alpha synergized in the activation of DC. Stimulated with a combination of ATP and TNF-alpha, DC expressed the maturation marker CD83, secreted large amounts of IL-12, and were potent stimulators of T cells. In the presence of the P2 receptor antagonist suramin, the effects of ATP were completely abolished. Our results suggest that extracellular ATP may play an important immunomodulatory role by activating DC and by skewing the immune reaction toward a Th1 response through the induction of IL-12 secretion.

Adenosine Triphosphate↗
PubMed2000

High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein.

Hypoxic pulmonary vasoconstriction is associated with but may not be sufficient for the development of high-altitude pulmonary oedema (HAPO). Hypoxia is known to induce an inflammatory response in immune cells and endothelial cells. It has been speculated that hypoxia-induced inflammatory cytokines at high altitude may contribute to the development of HAPO by causing capillary leakage in the lung. We were interested if such an inflammatory response, possibly involved in a later development of HAPO, is detectable at high altitude in individuals without HAPO. We examined the plasma levels of interleukin 6 (IL-6), interleukin 1 receptor antagonist (IL-1ra) and C-reactive protein (CRP) in two independent studies: study A, Jungfraujoch, Switzerland, three overnight stays at 3458 m, n=12; study B: Capanna Regina Margherita, Italy, 3 overnight stays at 3647 m and one overnight stay at 4559 m, n=10. In both studies, probands showed symptoms of acute mountain sickness but no signs of HAPO. At the Jungfraujoch, IL-6 increased from 0.1+/-0.03 pg/ml to 2. 0+/-0.5 pg/ml (day 2, P=0.03), IL-1ra from 101+/-21 to 284+/-73 pg/ml (day 2, P=0.01), and CRP from 1.0+/-0.4 to 5.8+/-1.5 micrograms/ml (day 4, P=0.01). At the Capanna Margherita, IL-6 increased from 0. 5+/-0.2 pg/ml to 2.0+/-0.8 pg/ml (P=0.02), IL-1ra from 118+/-25 to 213+/-28 pg/ml (P=0.02), and CRP from 0.4+/-0.03 to 3.5+/-1.1 micrograms/ml (P=0.03). IL-8 was below the detection limit of the ELISA (<25 pg/ml) in both studies. The increase of IL-6 and IL-1ra in response to high altitude was delayed and preceded the increase of CRP. We conclude that: (1) circulating IL-6, IL-1ra and CRP are upregulated in response to hypobaric hypoxic conditions at high altitude, and (2) the moderate systemic increase of these inflammatory markers may reflect considerable local inflammation. The existence and the kinetics of high altitude-induced cytokines found in this study support the hypothesis that inflammation is involved in the development of HAPO.

Adult↗
PubMed2000

[A combined PACS and Internet information system in a university medical center].

PURPOSE: The Department of Radiology at the University Hospital Innenstadt Munich provides all clinical departments of a large university hospital with several radiology units at different locations. During the last four years all units have been fully digitalized with a stepwise installation of a PACS. The PACS also processes images from the Nuclear Medicine Department. METHODS: As image modalities, archive systems and review workstations, we use devices from multiple vendors, which are integrated into a consistent system using the DICOM standard. The hospital has developed its own RIS and an Internet information system, which provides access to all reports and images from radiology for all clinical departments inside the hospital. Additionally, other clinical information such as laboratory results or ECG examinations are available through the system. RESULTS: After one year of operation, the system succeeded in the clinical routine work as the primary source for radiological reports and images as well as for laboratory values. CONCLUSION: The advantages of digitalization were, besides reduction of film cost, especially optimizations of work flow with access to digital images from everywhere at any time.

Academic Medical Centers↗
PubMed2000

Specific type IV phosphodiesterase inhibitor rolipram mitigates experimental colitis in mice.

The specific type IV phosphodiesterase inhibitor rolipram is a potent suppressor of tumor necrosis factor-alpha (TNF) synthesis. We examined the efficacy of rolipram for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice received 5% dextran sulfate sodium in their drinking water continuously for up to 11 days. Colitis was quantified by a clinical activity score assessing weight loss, stool consistency, and rectal bleeding (range from 0 to 4); by colon length; by a semiquantitative histologic score (range from 0 to 6); and by detecting TNF concentration in colonic tissue by enzyme-linked immunosorbent assay. In a first protocol, rolipram (10 mg/kg b.wt./day i.p.) was started on the same day as dextran sulfate sodium. Rolipram reduced the clinical activity of colitis (score 1.1 +/- 0.3) compared with mice that did not receive rolipram (2.4 +/- 0.4; P =.041). Rolipram also partially reversed the reduction of colon length (without rolipram, 12.4 +/- 0. 3 cm; with rolipram, 15.4 +/- 0.7 cm; P =.004) and improved the histologic score (1.5 +/- 0.6 in rolipram-treated mice versus 4.6 +/- 0.5; P =.020). Rolipram suppressed colonic tissue TNF concentrations. The beneficial effect of rolipram was confirmed in a second protocol in which dextran sulfate sodium exposure was discontinued on day 7 and rolipram was administered from day 8 through day 15. These three series of experiments on a total of 153 mice documented the efficacy of rolipram in both the prevention and treatment of experimental colitis.

Animals↗
PubMed2000

Suppression of TNF-alpha production in human mononuclear cells by an adenosine kinase inhibitor.

Adenosine exerts potent anti-inflammatory activities through inhibition of cytokine synthesis by activated monocytes. Adenosine is rapidly phosphorylated intracellularly by adenosine kinase. GP515, an adenosine kinase inhibitor, prevents the phosphorylation of adenosine to AMP and thereby locally enhances the adenosine concentration. GP515 has exhibited significant anti-inflammatory effects in several murine models of inflammation. In this study we investigated the effect of GP515 alone and in combination with exogenous adenosine or with rolipram, a phosphodiesterase inhibitor, on tumor necrosis factor alpha (TNF-alpha) synthesis in human peripheral blood mononuclear cells (PBMC) or whole blood. Lipopolysaccharide (LPS; 10 ng/mL)-stimulated PBMC were incubated in the absence or presence of these substances. GP515 alone showed a dose-dependent suppression of TNF-alpha production with an IC50 of 80 microM. The TNF-alpha-inhibiting effects of adenosine and GP515 were reversed in the presence of the cAMP antagonist (Rp)-cAMPS, supporting the hypothesis of a cAMP-mediated pathway. Combinations of GP515 with either adenosine or rolipram led to an additive inhibition of TNF-alpha synthesis. These experiments are the first to demonstrate efficacy of an adenosine kinase inhibitor in TNF-alpha suppression in cells of human origin. The findings form a basis to investigate these strategies in animal models of TNF-alpha-mediated chronic inflammatory diseases.

Adenosine↗
PubMed1999

Clindamycin and nicotinic neuromuscular transmission.

Upon clindamycin treatment a patient with Parkinson's disease showed marked tremor improvement which may be explained by clindamycin's ability to inhibit in-vitro nicotinergic, but not muscarinic signal transmission.

Animals↗
PubMed1999

NO-Donors, part 3: nitrooxyacylated thiosalicylates and salicylates - synthesis and biological activities(#).

Organic nitrates release nitric oxide when incubated with thiosalicylic acid. S-Nitrooxyacylated esters and amides of thiosalicylic acid, together with the corresponding salicylates, were synthesized in order to perform a first in vitro evaluation of these new nitrate-thiol-hybrid prodrugs. These prodrugs might release NO in vivo after biotransformation without the use of endogenous reductives. None of these prodrugs released NO spontaneously when dissolved in buffer solution, but they did activate soluble guanylyl cyclase and induced vasodilatation of phenylephrine-pretreated male Wistar rat aorta in a potency range between that of isosorbiddinitrate and glycerole trinitrate.

Journal Article↗
PubMed1999

Lipid treatment of inflammatory bowel disease.

The aetiology of inflammatory bowel disease remains unclear. Local mediators such as arachidonic acid metabolites and peptide mediators (cytokines) appear to contribute to the disease process. The successful administration of neutralizing antibodies against TNF-alpha has confirmed a pathophysiological role for this cytokine in Crohn's disease. Established therapy of inflammatory bowel disease with 5-aminosalicylic acid compounds has been shown to reduce local leukotriene B4 formation by inhibiting lipoxygenases. This therapeutic mechanism formed one rationale for examining the effect of n-3 fatty acids, which also inhibit leukotriene B4 formation, on the course of these diseases. In the first study, published in 1989, we found no beneficial effects of n-3 fatty acids in patients with Crohn's disease; however, there was clinical improvement, just falling short of significance, in patients with ulcerative colitis. Since then two uncontrolled and five controlled studies have further investigated the therapeutic effect of n-3 fatty acids in patients with ulcerative colitis. The size of the patient population in the controlled studies ranged from 10 to 96 patients in the largest study. Two of these studies showed a significant improvement in clinical activity and a steroid-sparing effect, respectively. Another study found only a trend towards improvement and one trial, which also included a treatment group receiving evening primrose oil, found no beneficial effect in the 16 patients receiving n-3 fatty acids. A large, 2 year trial of n-3 fatty acids in patients with ulcerative colitis off steroids, which was recently completed at the Universities of Munich and Mainz, showed a delay of the first episode of relapse, but no reduction in the cumulative relapse rate at 2 years. Controversial results have been published for Crohn's disease. A new enteric-coated formulation reportedly increased the proportion of patients in remission where as another trial using a conventional preparation found no significant effect.

Colitis, Ulcerative↗
PubMed1998

Anti-inflammatory activities of cAMP-elevating agents: enhancement of IL-10 synthesis and concurrent suppression of TNF production.

Interleukin-10 (IL-10) and tumor necrosis factor (TNF) exert key roles in some acute and chronic inflammatory diseases. In this study we investigated (1) the potency of different cAMP-elevating agents in enhancing IL-10 synthesis, (2) the involvement of protein kinase A in this enhancement, and (3) the mutual dependence of cAMP-enhanced IL-10 formation and cAMP-suppressed TNF synthesis. Rolipram, a specific phosphodiesterase inhibitor and cicaprost, a prostacyclin analogue, were applied as cAMP-elevating agents. The stable cAMP antagonist (Rp)-cAMPS was used to abrogate activation of protein kinase A. Human peripheral blood mononuclear cells were stimulated with lipopolysaccharide (LPS). TNF was quantified by radioimmunoassay, IL-10 by enzyme-linked immunosorbent assay, and mRNA by reverse transcriptase-polymerase chain reaction. After LPS stimulation alone 253+/-45 pg/mL IL-10 was synthesized, which increased to 644+/-117 pg/mL in the presence of 1 microM rolipram. (Rp)-cAMPS reversed this increase of IL-10 formation. In the same samples, the LPS-stimulated production of TNF was markedly attenuated by rolipram or cicaprost. A kinetic analysis revealed a significant increase in TNF production before IL-10 formation was detectable. These results demonstrate that (1) cAMP-elevating agents enhance IL-10 synthesis and suppress TNF production; (2) these regulative functions of cAMP-elevating agents are mediated by activation of protein kinases A; (3) suppression of TNF synthesis by cAMP in the early phase is not mediated by endogenous IL-10. Taken together, rolipram and cicaprost exert a dual regulatory function by enhancing IL-10 formation and attenuating TNF synthesis.

Cyclic AMP↗
PubMed1998

The hairy cell leukemia cell line Eskol spontaneously synthesizes tumor necrosis factor-alpha and nitric oxide.

Tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) exert a wide array of immunoregulatory, partly related effects. We examined the production of these two mediators by the human hairy cell leukemia cell line Eskol. Combined cell lysate and supernatant of Eskol cells (0.5 x 10(6) cells ml(-1)) incubated for 18 h, contained a mean of 1.5 ng ml(-1) TNF-alpha. This spontaneous TNF-alpha synthesis was enhanced by phorbol ester (PMA) and phytohemagglutinin (PHA) and decreased by dexamethasone. Nitrite, the stable product of NO, accumulated in the supernatant of Eskol cells after prolonged incubation. Maximal nitrite concentrations (range: 0.8-3.5 microM at 2 x 10(6) cells ml(-1)) were detected after 7 days of incubation. NO production was augmented by PHA and reduced by PMA. The inhibitors of NO synthase N(G)-monomethyl-L-arginine (L-NMMA) and aminoguanidine decreased NO synthesis. Simultaneous activation with the proinflammatory cytokines, interferon-gamma, interleukin-1beta and TNF-alpha, increased NO synthesis. These results suggest that NO production in Eskol cells results from inducible NO synthase activity. This is the first direct demonstration of NO formation in human lymphoid cells. The cell line, Eskol, may serve as a model to study regulation of TNF-alpha and NO synthesis in human B-cell leukemia.

Dexamethasone↗
PubMed1998

Nitric oxide downregulates tumour necrosis factor in mRNA in RAW 264.7 cells.

Nitric oxide (NO) and tumour necrosis factor (TNF) are essential mediators in a number of biological processes, including the immune response. TNF stimulates NO production via expression of inducible NO synthase (iNOS), with L-arginine being the only substrate. Previously, we demonstrated that, inversely, NO inhibits lipopolysaccharide (LPS)-induced TNF synthesis. We have now investigated whether this reduction of TNF bioactivity is also reflected at the level of TNF mRNA in the murine macrophage cell line RAW 264.7. TNF mRNA was quantified by Northern analysis using an alpha[33P]dCTP-labelled probe. Cells stimulated with 10 microg/ml LPS in the absence of L-arginine, in order to prevent endogenous NO formation, contained more TNF mRNA than cells supplied with 1 mM L-arginine at 14 h and 20 h after stimulation. By contrast, no difference was observed at 4 h. This time course is compatible with the involvement of iNOS. The half-life of TNF mRNA in the presence of NO was roughly half that observed under L-arginine-free conditions (41 min versus 77 min, respectively). L-citrulline (1 mM), which has been shown to be recycled in RAW 264.7 cells to L-arginine, completely restored attenuation of TNF bioactivity and TNF message to control levels obtained with 1 mM L-arginine. Together, these findings suggest that endogenous NO regulates TNF mRNA, mainly by reducing its half-life. In addition, a distinct additional band (approximately 1.4 kb) hybridizing with the TNF probe was consistently observed in non-stimulated cells. This may correspond to TNF mRNA specifically hydrolysed at the AU-rich region, possibly reflecting another control point for TNF expression.

Animals↗
PubMed1998

Inflammatory bowel disease: no association between allele combinations of the interleukin (IL) I beta and IL-I receptor antagonist gene polymorphisms.

BACKGROUND: Interleukin 1 (IL-1) and its physiological antagonist interleukin-1 receptor antagonist (IL-1 ra) play a crucial role in the pathogenesis of inflammatory bowel disease. Polymorphisms in the genes coding for these cytokines, the restriction enzyme TaqI polymorphism for IL-1 beta and the variable number of tandem repeats (VNTR) polymorphism for IL-1 ra, have been shown to influence cytokine synthesis in vitro. Recently, an association has been described for distinct allele combinations of these two polymorphisms in patients with ulcerative colitis and with Crohn's disease but not in healthy control subjects. METHODS: We studied 56 patients with ulcerative colitis, 64 patients with Crohn's disease and 196 healthy control subjects. All were unrelated Caucasians of European ancestry. After polymerase chain reaction (PCR) the amplification products were analysed on agarose gels. For the IL-1 beta polymorphism the PCR product was additionally digested using the restriction enzyme TaqI. RESULTS: The allele and genotype frequencies as well as the carriage rates of the IL-1 beta TaqI polymorphism in healthy control subjects were in agreement with previous findings in other populations. Allele and genotype frequencies of the IL-1 beta polymorphism were not different in inflammatory bowel disease patients compared with healthy control subjects. Comparing allele combinations of both polymorphisms no association could be identified either within healthy control subjects or in the groups of patients with ulcerative colitis or Crohn's disease. CONCLUSION: Thus, we could not confirm the results of a previous study reporting an association between the IL-1ra and IL-1 beta gene polymorphisms in patients with inflammatory bowel disease.

Adult↗
PubMed1998

In vivo synthesis of tumor necrosis factor-alpha in healthy humans after live yellow fever vaccination.

Most knowledge about the synthesis of human tumor necrosis factor (TNF)-alpha and its regulation derives from in vitro studies. The hypothesis that the syndrome of malaise, myalgia, and low fever observed after a vaccination with live attenuated yellow fever virus could be associated with increased synthesis of TNF was investigated. Plasma samples of 15 healthy subjects taken before and until day 2 (until day 11 in 5 of these subjects) after yellow fever vaccination, showed a significant increase of plasma TNF concentration on day 2 after vaccination and a second peak on day 7. Interleukin-1 receptor antagonist (IL-1ra) concentration was significantly elevated in all subjects on day 2 after vaccination. In a control group receiving non-live vaccinations, TNF and IL-1ra concentrations were unchanged. Thus, yellow fever vaccination represents a routine medical intervention that results in a reproducible increase in the plasma concentration of TNF and secondary cytokines. This may serve as a unique model for the study of the regulation of TNF synthesis in vivo.

Adult↗