Biomedical subjects

Arthur Kaser

Publications and source records attributed to Arthur Kaser.

30 records · Page 2Linked to original sources

PubMed2003

Interleukin-18 attracts plasmacytoid dendritic cells (DC2s) and promotes Th1 induction by DC2s through IL-18 receptor expression.

In vivo evidence suggests that interleukin-18 (IL-18) shapes the development of adaptive immunity toward T-helper cell type 1 (Th1) responses. Monocyte-derived dendritic cells 1 (DC1s) preferentially induce a Th1 response, while plasmacytoid DC-derived DC2s have been linked to a Th2 response. We analyzed the role of IL-18 during the initiation phase of a Th response in vitro to elucidate the basis of these in vivo observations. IL-18 was constitutively released from DC1s, but not DC2s. Neutralization of IL-18 in coculture experiments of DC1s with allogeneic naive T lymphocytes did not alter the Th1/Th2 phenotype, while anti-IL-12 efficiently down-regulated the Th1 response. Unexpectedly, IL-18 receptor (IL-18R) alpha and beta chains were expressed on DC2 lineage. IL-18R expression was functional, as IL-18 induced chemotaxis in plasmacytoid DCs (pre-DC2s) and enhanced the allostimulatory capacity of IL-3-differentiated DC2s. Pre-DC2s exposed to IL-18 skewed the development of Th cells toward Th1 in coculture experiments of DC2s and allogeneic naive T cells, which was inhibited by IL-12 p70 neutralization. IL-18 might have a profound role during the initiation phase of an immune response by recruiting pre-DC2s and modulating the function of DC2s.

Apoptosis↗

PubMed2003

Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis.

BACKGROUND/AIMS: Severe alcoholic hepatitis (AH) is associated with high mortality. Tumor necrosis factor-alpha (TNFalpha) has been demonstrated to play an important role in its pathophysiology. METHODS: Twelve patients with biopsy-confirmed AH and a Maddrey discriminant factor >32 were treated with a single infusion of the anti-TNF monoclonal antibody Infliximab at a dose of 5mg/kg body weight. Serial measurements were made for various cytokines using specific enzyme-linked immunoassays (ELISA). In four patients, liver biopsy samples were available pretreatment and on day+28 of therapy. RESULTS: Ten of the 12 patients are alive at a median of 15 (12-20) months. Two patients died within 30 days from septicemia. Serum bilirubin levels, Maddrey score, neutrophil count and C-reactive protein fell significantly within the first month. There was an early, though not significant, decrease in plasma levels of proinflammatory cytokines (interleukins (IL)-1beta, IL-6, IL-8, interferon-gamma), whereas plasma levels of TNFalpha remained near the sensitivity limit of the assay throughout the treatment course. While TNFalpha mRNA expression in the liver did not change, expression of IL-8, a cytokine regulated mainly by TNFalpha, was almost absent on day+28. CONCLUSIONS: Our data suggest that randomized controlled trials of anti-TNF antibody in severe AH are warranted.

Antibodies, Monoclonal↗

PubMed2003

Sphingosine kinase-dependent migration of immature dendritic cells in response to neurotoxic prion protein fragment.

The concept that circulating dendritic cells mediate neuroinvasion in transmissible spongiform encephalopathies received strong support from recent observations that prion protein is expressed in myeloid dendritic cells. We observed that prion protein fragment 106-126 is a chemoattractant for monocyte-derived immature but not mature dendritic cells. Signaling events in chemotaxis involved enzymes downstream of G(q) protein and were inhibited by blockade of sphingosine kinase, suggesting transactivation of sphingosine-1-phosphate-dependent cell motility by prion protein.

Animals↗

PubMed2003

Pathways for the regulation of interferon-gamma-inducible genes by iron in human monocytic cells.

To elucidate iron-regulated interferon-gamma (IFN-gamma) effector functions, we investigated three IFN-gamma-inducible genes [intercellular adhesion molecule-1 (ICAM-1), human leukocyte antigen (HLA)-DR, guanosine 5'-triphosphate-cyclohydrolase I (GTP-CH)] in primary human monocytes and the cell line THP-1. IFN-gamma increased the surface expression of ICAM-1 and HLA-DR and stimulated GTP-CH activity. Addition of iron before cytokine stimulation resulted in a dose-dependent reduction of these pathways, and iron restriction by desferrioxamine (DFO) enhanced ICAM-1, HLA-DR, and GTP-CH expression. Iron neither affected IFN-gamma binding to its receptor nor IFN-gamma receptor surface expression. IFN-gamma-inducible mRNA expression of ICAM-1, HLA-DR, and GTP-CH was reduced by iron and increased by DFO by a transcriptional mechanism. Moreover, ICAM-1 and to a lesser extent, GTP-CH and HLA-DR mRNA expression were regulated post-transcriptionally, as iron pretreatment resulted in shortening the mRNA half-life compared with cells treated with IFN-gamma alone. Thus, iron perturbations regulate IFN-gamma effector pathways by transcriptional and post-transcriptional mechanisms, indicating that iron rather interferes with IFN-gamma signal-transduction processes.

Blotting, Northern↗

PubMed2002

Role of IL-10 for induction of anemia during inflammation.

Anemia is frequently observed in patients suffering from chronic inflammatory disorders. Recent in vitro data suggest that Th2 cytokines, such as IL-10, could be involved in its pathogenesis. We analyzed 1) changes in hemoglobin values in 329 patients with chronic active Crohn's disease receiving the anti-inflammatory cytokine IL-10 as part of a randomized, double-blind, placebo-controlled study, 2) serum iron parameters in a subgroup of these patients (n = 54), and 3) the in vitro effects of IL-10 on ferritin transcription and translation in human monocytic cells (THP-1) by means of Northern blot and immunoprecipitation after metabolic labeling. Patients receiving higher doses of IL-10 developed anemia and presented with a dose-dependent increase of ferritin and soluble transferrin receptor levels, an indicator of iron restriction to erythroid progenitor cells. According to our in vitro data, hyperferritinemia may result from direct stimulation of ferritin translation by IL-10 in activated monocytic cells, most likely by cytokine-mediated reduction of the binding affinity of translational repressors, iron-regulatory proteins, to the 5'-untranslated region of ferritin mRNA. In patients, all observed changes were most pronounced at the end of therapy (day +29), and thereafter hemoglobin levels and serum iron parameters returned to baseline levels within 4 wk of follow-up. Our data demonstrate that IL-10 causes anemia in patients with inflammatory bowel disease which may be referred to the induction of imbalances in iron homeostasis by the cytokine, leading to hyperferritinemia and limited iron availability to erythroid progenitor cells, a condition typically seen in the anemia of chronic inflammation.

Adolescent↗

PubMed2002

Plasma levels of interleukin-18 and interleukin-18 binding protein are elevated in patients with chronic liver disease.

Interleukin 18 (IL-18) is a recently described proinflammatory cytokine. In mouse models it has been shown to play a key role in the development of liver injury. IL-18 binding protein (IL-18BP) is a naturally occurring antagonist of IL-18. In this study we investigated whether IL-18/IL-18BP levels are altered in patients with chronic liver disease (CLD). We measured IL-18 and IL-18BP plasma levels in 153 patients with CLD and 41 healthy controls by a specific ELISA. Plasma levels of IL-18 were significantly higher in CLD patients than in healthy controls. Cirrhotics had higher levels than noncirrhotics. IL-18 levels increased with disease progression. IL-18BP plasma levels paralled the increase of IL-18 with disease progression, except in stage Child C cirrhosis. IL-18 and IL-18BP levels were elevated independent of the etiology of CLD. IL-18 and IL-18BP correlated with laboratory parameters of inflammation and liver injury. Plasma levels of IL-18 and its antagonist, IL-18BP, are elevated in CLD and correlate with severity of disease. IL-18BP may not be sufficient to counteract the overwhelming proinflammatory response in end stage liver disease.

Adult↗

PubMed2002

Endotoxin and its binding proteins in chronic liver disease: the effect of transjugular intrahepatic portosystemic shunting.

BACKGROUND: Gut-derived endotoxin is insufficiently cleared by the diseased liver, and thus, is elevated in plasma of patients with chronic liver disease (CLD). Endotoxin action might be modified by binding to soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP), both of which have not yet been sufficiently studied in CLD. METHODS: Endotoxin, sCD14 and LBP have been determined in peripheral blood of 72 patients and 39 control subjects, and in portal and hepatic venous blood of 12 patients during transjugular intrahepatic portosystemic shunt (TIPS) implantation. RESULTS: Peripheral endotoxin (average 3-fold increased compared to controls), LBP, and sCD14 plasma levels were elevated in chronic liver disease irrespective of Child stage m, preserve/absence of cirrhosis or aetiology. LBP, and sCD14. Furthermore, endotoxin levels in the portal vein (38.1 +/- 6.1 pg/ml) were only slightly elevated compared to the hepatic vein (29.2 +/- 4.4 pg/ml), and peripheral endotoxin levels did not increase after TIPS. CONCLUSIONS: Decreased hepatocellular function rather than hepatic blood shunting might be responsible for endotoxemia. The elevation in LBP and sCD14 levels may be a consequence of endotoxemia.

Acute-Phase Proteins↗

PubMed2002

Antitumour necrosis factor therapy in Crohn's disease.

The key role and contribution of various pro-inflammatory cytokines in common chronic inflammatory disorders such as inflammatory bowel disease (IBD) has been thoroughly investigated in recent years. Besides IL-1, TNF-alpha has been identified as one of the central immune mediators controlling inflammatory processes. Not surprisingly, neutralisation of these cytokines has been introduced into clinical research. Crohn's disease (CD) is one of the chronic inflammatory disorders where TNF-alpha seems to have a particularly important role. Neutralisation of this cytokine by specific antibodies, for example infliximab, has been shown recently to affect the clinical phenotype of this disorder. Other TNF-neutralising approaches such as etanercept have also been studied in patients with CD but with less successful outcomes. These new cytokine-targeting approaches have changed clinical medicine in the field of inflammatory disorders.

Antibodies, Monoclonal↗

PubMedDate not supplied

Mechanisms of iron mediated regulation of the duodenal iron transporters divalent metal transporter 1 and ferroportin 1.

Intestinal iron absorption is regulated by the body's demands for iron. Identification of divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1) has improved our understanding of iron transport across the intestinal epithelium. Although DMT1 and FPN1 mRNA bear an iron responsive element (IRE) within its untranslated regions which should cause susceptibility to iron mediated posttranscriptional regulation the latter has not been shown so far. The effects of iron perturbations on DMT1 and FPN1 expression were investigated in CaCo2 cells and in primary tissue cultures of human duodenal biopsies by means of Northern Blot, Western Blot, RNA-bandshift and Nuclear Run off analysis. Both DMT1 and FPN1 mRNA levels were increased upon treatment of CaCo2 cells with desferrioxamine, whereas iron treatment resulted in the opposite effect. These changes were paralleled by the respective alterations in DMT1 and FPN1 protein expression. Although desferrioxamine treatment increased the binding affinity of iron regulatory protein-1 to DMT1- and FPN1-IRE, the mRNA half life of DMT1 mRNA remained unchanged. Nuclear run-off analysis then demonstrated that the effects of iron and desferrioxamine on DMT1 and FPN1 mRNA expression are rather due to modulation of transcription of these genes. Our results demonstrate that iron unidirectionally regulates the expression of the two ferrous ion transporters DMT1 and FPN1 by affecting their transcription. This provides evidence for a negative feed-back loop between intracellular iron availability and transmembrane iron transport.

Caco-2 Cells↗

PubMedDate not supplied

Interferon-alpha suppresses leptin levels: studies in interferon-alpha treated patients with hepatitis C virus infection and murine adipocytes.

Leptin is an adipocyte-derived protein, which signals the status of current energy stores and energy intake to the central nervous system. Interferon-alpha therapy is frequently associated with loss of appetite and weight reduction. In this study, we tested whether interferon-alpha is able to regulate leptin synthesis. We therefore determined leptin plasma concentrations in thirteen patients with chronic hepatitis C who were treated with 1 x 10(7) IU interferon-alpha daily, up to 21 days after initial treatment. Furthermore, leptin concentrations and messenger RNA levels were quantified in interferon-alpha-treated and untreated murine adipocytes. After reaching peak plasma levels at 12 hours, probably reflecting the circadian rhythm, leptin concentrations fell and were significantly lower after 14 days. They remained significantly decreased 17 and 21 days after the start of the interferon-alpha treatment. In murine adipocytes exposed to interferon-alpha, leptin secretion was significantly decreased while messenger RNA levels remained unchanged. Our data suggest that, in contrast to proinflammatory cytokines such as interleukin-1, interferon-alpha suppresses leptin secretion in adipose tissue. We therefore hypothesize that loss of weight and appetite in interferon-alpha-treated patients with chronic hepatitis C might not be due to an elevation of leptin resulting in signals of increased energy stores in the brain.

3T3 Cells↗

PubMedDate not supplied

Anti-inflammatory effects of hepatocyte growth factor: induction of interleukin-1 receptor antagonist.

Hepatocyte growth factor (HGF) prevents liver failure in various animal models including endotoxin-induced acute liver failure. We were interested to find out whether human HGF exerts anti-inflammatory effects by modulation of cytokine synthesis. Therefore, human HepG2 cells were cultured with increasing concentrations of HGF. HGF dose-dependently upregulated the production of interleukin-1 receptor antagonist (IL-1Ra). Incubation of HepG2 cells with interleukin-1beta (IL-1beta) caused an increase in IL-1Ra levels, while interleukin-6 (IL-6) had no effect on IL-1Ra synthesis. Co-stimulation of HepG2 cells with HGF + IL-1beta resulted in a synergistic effect on IL-1Ra mRNA and protein expression. Stimulation of freshly isolated mouse hepatocytes from male C57 BL/6 mice with HGF increased IL-1Ra mRNA and protein synthesis dose-dependently. A co-stimulation with HGF and IL-1beta had a synergistic effect on IL-1Ra mRNA expression but only a partially additive effect on IL-1Ra protein synthesis. HGF-induced IL-1Ra production was significantly decreased by the mitogen-activated protein kinase (MAPK) inhibitor PD98059. Accordingly, HGF stimulation specifically increased MAPK-dependent signalling pathway (p42/44). In contrast, in preactivated PBMC mRNA expression and protein synthesis of IL-1Ra, interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-alpha) were unaffected after stimulation with HGF. In conclusion, our data suggest that HGF exerts anti-inflammatory effects by modulating the signal transduction cascade leading to increased expression of IL-1Ra, which might explain the protective and regenerative properties of this cytokine in animal models of liver failure.

Animals↗

PubMedDate not supplied

Elevated systemic levels of free interleukin-18 (IL-18) in patients with Crohn's disease.

OBJECTIVES: Interleukin 18 (IL-18) is a proinflammatory cytokine and a member of the IL-1 family. Animal models and investigations in humans point to an important role for this cytokine in inflammatory bowel diseases (IBD). IL-18 binding protein (IL-18BP) is a naturally occurring antagonist of IL-18. Methods. In this study, we measured IL-18 and IL-18BP plasma concentrations and spontaneous release in cultures of colonic explants from healthy subjects (n = 41), patients with Crohn's disease (CD, n = 135), and patients with ulcerative colitis (UC, n = 93). RESULTS: Both CD and UC patients had higher IL-18BP plasma levels than controls. Plasma levels of free, unbound IL-18 were significantly elevated in CD patients compared to healthy controls, but not in UC patients. Colonic explant cultures from inflamed areas in IBD patients released significantly higher levels of IL-18 than non-inflamed areas and controls. IL-18BP levels from the same cultures were below the detection limit over a culture period of 24 h. CONCLUSIONS: Our results confirm the importance of IL-18 in the pathogenesis of IBD and suggest that especially in CD, IL-18BP might be produced in insufficient quantities to counteract the effects of endogenous IL-18.

Adolescent↗