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H Tilg

Publications and source records attributed to H Tilg.

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

Infliximab in severe steroid-refractory ulcerative colitis: a pilot study.

Tumor necrosis factor-alpha (TNF alpha)-neutralization by infliximab has previously proven efficacious in chronic active Crohn's disease (CD). We performed an open-label pilot study of a single infusion of 5 mg/kg infliximab in six patients with severe active, steroid-refractory ulcerative colitis (UC). Clinical activity was evaluated according to Lichtiger on days -1, day 7, and day 28. Colonoscopy with biopsy was performed on day -1 and day 7. All patients showed marked clinical improvement by day 7 (Lichtiger score 16.3 +/- 0.4 [day -1] vs 4.8 +/- 0.7 [day 7], p < 0.0001). Four of six patients had long-term remission (Lichtiger score 7.7 +/- 2.2 [day 28], P < 0.01 compared to day -1), with a median follow-up of 5.5 months. Colonoscopy confirmed significant healing of endoscopic lesions. The inflammatory infiltrate disappeared on H&E stains, with a marked reduction in infiltrating neutrophils. Semiquantitative evaluation of T and B lymphocytes and macrophages by immunohistochemistry did not reveal major differences compared to pre-treatment. Apoptotic cells in the mucosa were reduced on day 7. Our data point toward a novel efficacious treatment option in severe steroid-refractory UC and raise the need for controlled trials.

Adult↗
PubMed2001

Engagement of the Fc epsilon RI stimulates the production of IL-16 in Langerhans cell-like dendritic cells.

Preferential uptake and presentation of IgE-bound allergens by epidermal Langerhans cells (LC) via the high affinity IgE receptor, FcepsilonRI, is regarded as an important mechanism in the induction of cutaneous inflammation in atopic dermatitis. Here, we show that activation of monocyte-derived LC-like dendritic cells (LLDC) through engagement of FcepsilonRI induces the expression of IL-16, a chemoattractant factor for dendritic cells, CD4+ T cells, and eosinophils. We found that ligation of FcepsilonRI on LLDC derived from atopic dermatitis patients that express high levels of FcepsilonRI increases IL-16 mRNA expression and storage of intracellular IL-16 protein and enhances the secretion of mature IL-16 in a biphasic manner. An early release of IL-16 (peak at 4 h) is independent of protein synthesis, while a more delayed release (peak at 12 h) requires protein synthesis and occurs subsequent to the induction of IL-16 mRNA and intracellular accumulation of pro-IL-16. There was evidence that LLDC use caspase-1 to process IL-16, as inhibition of caspase-1, but not of caspase-3, partially prevented the release of IL-16 in response to ligation of FcepsilonRI. In an in vivo model of IgE-dependent LC activation, the atopy patch test, positive skin reactions were also associated with the induction of IL-16 in epidermal dendritic cells. These data indicate that IL-16 released from LC after allergen-mediated activation through FcepsilonRI may link IgE-driven and cellular inflammatory responses in diseases such as atopic dermatitis.

Caspase 1↗
PubMed2001

Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis.

Baseline platelet production is dependent on thrombopoietin (TPO). TPO is constitutively produced and primarily regulated by receptor-mediated uptake by platelets. Inflammatory thrombocytosis is thought to be related to increased interleukin-6 (IL-6) levels. To address whether IL-6 might act through TPO to increase platelet counts, TPO was neutralized in vivo in C57BL/10 mice treated with IL-6, and hepatic TPO mRNA expression and TPO plasma levels were studied. Transcriptional regulation of TPO mRNA was studied in the hepatoblastoma cell line HepG2. Furthermore, TPO plasma levels were determined in IL-6-treated cancer patients. It is shown that IL-6-induced thrombocytosis in C57BL/10 mice is accompanied by enhanced hepatic TPO mRNA expression and elevated TPO plasma levels. Administration of IL-6 to cancer patients results in a corresponding increase in TPO plasma levels. IL-6 enhances TPO mRNA transcription in HepG2 cells. IL-6-induced thrombocytosis can be abrogated by neutralization of TPO, suggesting that IL-6 induces thrombocytosis through TPO. A novel pathway of TPO regulation by the inflammatory mediator IL-6 is proposed, indicating that the number of platelets by themselves might not be the sole determinant of circulating TPO levels and thus of thrombopoiesis. This regulatory pathway might be of relevance for the understanding of reactive thrombocytosis.

Animals↗
PubMed2001

Cutting edge: peripheral neuropeptides attract immature and arrest mature blood-derived dendritic cells.

Dendritic cells (DC) are highly motile and play a key role in mediating immune responses in various tissues and lymphatic organs. We investigated locomotion of mononuclear cell-derived DC at different maturation stages toward gradients of sensory neuropeptides in vitro. Calcitonin gene-related peptide, vasoactive intestinal polypeptide, secretin, and secretoneurin induced immature DC chemotaxis comparable to the potency of RANTES, whereas substance P and macrophage-inflammatory protein-3beta stimulated immature cell migration only slightly. Checkerboard analyses revealed a true chemotactic response induced by neuropeptides. Upon maturation of DC, neuropeptides inhibited spontaneous, macrophage-inflammatory protein-3beta- and 6Ckine-induced cell migration. Maturation-dependent changes in migratory behavior coincided with distinct neuropeptide-induced signal transduction in DC. Peripheral neuropeptides might guide immature DC to peripheral nerve fibers where high concentrations of these peptides can arrest the meanwhile matured cells. It seems that one function of sensory nerves is to fasten DC at sites of inflammation.

Calcitonin Gene-Related Peptide↗
PubMed2001

Interleukin-16 supports the migration of Langerhans cells, partly in a CD4-independent way.

Migration of cutaneous dendritic cells is essential for the induction of primary immune responses. Chemotaxis plays an important part in guiding migrating cells through the skin. Therefore, we investigated the influence of interleukin-16, a potent chemoattractant, on the migratory properties of cutaneous dendritic cells. Interleukin-16 added to murine and human skin explant cultures, enhanced emigration of Langerhans cells as well as dermal dendritic cells out of the skin. In contrast to tumor necrosis factor-alpha, intradermally injected interleukin-16 did not reduce the density of Langerhans cells suggesting a chemotactic rather than a mechanistic migration-inducing effect of interleukin-16. In support of these findings, the known migration-promoting effect of tumor necrosis factor-alpha in skin explant cultures could be neutralized by anti-interleukin-16 antibody and vice versa, indicating different but cooperative ways of action for both cytokines. In whole skin explant cultures blocking of the interleukin-16 effect was also achieved with a monoclonal antibody against CD4, the receptor for interleukin-16. In contrast, in cultures of murine epidermis alone no blocking by anti-CD4 became obvious and in CD4-deficient mice Langerhans cell migration in response to interleukin-16 was maintained. This suggests that another receptor for interleukin-16 might be operative for Langerhans cells in the mouse epidermis. Finally, we detected interleukin-16-positive cells in the dermis of skin explants, tumor necrosis factor-alpha-treated and contact allergen-treated skin. Taken together, it seems likely that locally secreted interleukin-16 might serve to enhance the migration of cutaneous dendritic cells and optimize the response to foreign antigen encountering the skin.

Animals↗
PubMed2001

Cytokines and liver diseases.

Cytokines are pleiotropic peptides produced by virtually every nucleated cell in the body. In most tissues, including the liver, constitutive production of cytokines is absent or minimal. There is increasing evidence that several cytokines mediate hepatic inflammation, apoptosis and necrosis of liver cells, cholestasis and fibrosis. Interestingly, the same mediators also mediate the regeneration of liver tissue after injury. Among the various cytokines, the proinflammatory cytokine tumour necrosis factor-alpha (TNF-a) has emerged as a key factor in various aspects of liver disease, such as cachexia and/or cholestasis. Thus, antagonism of TNF-a and other injury-related cytokines in liver diseases merits evaluation as a treatment of these diseases. However, because the same cytokines are also necessary for the regeneration of the tissue after the liver has been injured, inhibition of these mediators might impair hepatic recovery. The near future will bring the exiting clinical challenge of testing new anticytokine strategies in various liver diseases.

Animals↗
PubMed2001

Interferon-alpha in inflammation and immunity.

Type I interferons, constituting IFN-alpha and IFN-beta, were initially described for their ability to interfere with viral replication. IFN-alpha was the first cytokine to be cloned and used successfully as a therapeutic cytokine, although its mechanism of action remained largely elusive. Evidence gathered over the last few years shed light on the molecular effects of IFN-alpha, especially its interaction with the cytokine cascade. Recently, the principle source of IFN-alpha could be identified as the precursor of type 2 dendritic cells, and IFN-alpha has been identified as the cytokine linking innate with adaptive immunity via its interaction with dendritic cells.

Animals↗
PubMed2000

B lymphocyte-derived IL-16 attracts dendritic cells and Th cells.

Interaction of B lymphocytes with Th cells is a fundamental step in the establishment of humoral immunity, and recent evidence suggests that direct interaction between B lymphocytes and dendritic cells (DCs) is also an important prerequisite. Factors involved in the selective recruitment of Th cells and DCs by B lymphocytes are insufficiently defined. We set out to delineate the role of IL-16, the soluble ligand of CD4, which is expressed on Th cells and DCs. B lymphocytes express IL-16 mRNA and synthesize bioactive IL-16 protein, and IL-16 is expressed in lymph node follicles in situ. B lymphocyte supernatant efficiently induces migration of CD4+ Th cells, monocyte-derived DCs, and circulating blood DCs in nitrocellulose filter-based assays. Neutralization of IL-16 bioactivity strongly inhibits this migratory response, suggesting that IL-16 might be a major chemotactic factor derived from B cells. The present data further support the idea that IL-16 might have a role in the initiation of cellular as well as humoral immunity by mediating the cellular cross-talk among T lymphocytes, B cells, and DCs, leading to recruitment of these cell types at common anatomical sites.

B-Lymphocytes↗
PubMed2000

Dendritic cell migration in different micropore filter assays.

Dendritic cells (DC) are highly motile and have been shown to migrate in vitro or in vivo towards various chemoattractants. Micropore filter methods with polycarbonate filters are generally used in these in vitro experiments. Among others, the main drawback of these filters is their thickness, which does not allow any assessment of effects of absolute concentration compared to gradients. The aim of this study was to establish a chemotaxis assay for dendritic cells using nitrocellulose filters, which can be adapted for checkerboard studies to distinguish between chemokinesis and chemotaxis. Immature DC were generated by culture of peripheral blood mononuclear cells using granulocyte-macrophage colony-stimulating factor and interleukin-4. We tested cell migration into nitrocellulose in a Boyden microchemotaxis chamber (leading front assay) and compared this method to the commonly used polycarbonate filter technique. Dendritic cells migrated well into nitrocellulose towards gradients of formyl peptide, complement fragment 5a, and monocyte chemotactic protein-3. The nitrocellulose method appeared to be more sensitive as compared to experiments testing migration across polycarbonate filters. Subsequent checkerboard analyses confirmed chemotactic activities of formyl peptide and complement fragment 5a. However, depending on the assay system, chemotaxis in polycarbonate filters but chemokinesis in nitrocellulose filters were observed for monocyte chemotactic protein-3. Measurement of DC migration in a cellulose nitrate micropore filter assay is more sensitive than the commonly used polycarbonate method and can be adapted for checkerboard analyses.

Chemokine CCL7↗
PubMed2000

Hepatocyte growth factor plasma levels after myocardial infarction are not affected by recombinant tissue-type plasminogen-activator therapy.

Hepatocyte growth factor (HGF), a cytokine involved in tissue regeneration, angiogenesis and lateral vessel growth, is secreted as a biological-inactive, single-chain precursor named pro-HGF. In case, of tissue injury pro-HGF is proteolytically cleaved at the extracellular locus by serine proteases. Results obtained from in vitro experiments showed that urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) can cleave single-chain HGF. In this study we measured serum HGF levels in patients with acute myocardial infarction (MCI). Two groups of patients were compared. One group (n = 7) was treated with a conventional therapy and the other group (n = 7) was subjected to a thrombolytic therapy with recombinant tissue-type plasminogen activator (rtPA). Serum samples were collected at time of admission and subsequently 12-16 hours, 20-30 hours and 50-60 hours after onset of chest pain. At admission and before administration of rtPA, serum HGF levels peaked at 16.8 +/- 2.2 ng/ml in the lysed group and at 20.7 +/- 6.5 ng/ml in the non-lysed group. Levels then continuously declined, reaching lowest values 50-60 hours after onset of chest pain (3.2 +/- 1.3 ng/ml in the group treated with rtPA versus 4.4 +/- 0.9 ng/ml in the non-lysed group). No statistical significant difference could be detected between the two groups at any time. We suggest that serine proteases other than tPA are involved in HGF activation in vivo.

Acute Disease↗
PubMed2000

In vivo effects of recombinant human interleukin-10 on lymphocyte phenotypes and leukocyte activation markers in inflammatory bowel disease.

BACKGROUND: Interleukin-10 (IL-10) exhibits potent anti-inflammatory and immunosuppressive activities in vitro. Recent data indicate that treatment with recombinant human IL-10 (rHuIL-10) Crohn's disease is safe and may induce clinical and endoscopic remission. The present study investigates the in vivo immunomodulatory properties of rHuIL-10 in inflammatory bowel disease (IBD). METHODS: As part of two randomized, double-blinded, placebo-controlled trials, repeated flow cytometric analyses of lymphocyte phenotypes (CD3, CD4, CD8, CD16 + 56, CD19) and activity markers (human leukocyte antigen [HLA]-DR; intercellular adhesion molecule-1 [ICAM-1]; IL-2-receptor alpha [IL-2R alpha]; high affinity receptor for immunoglobulin G [IgG; Fc gamma RI]) on T cells, monocytes, and neutrophils were performed in 17 patients with IBD who received rHuIL-10 (5, 10, or 20 micrograms/kg) or placebo, administered subcutaneously, once daily for 28 days. RESULTS: Minor changes were noted in CD3+, CD8+, and CD3+/CD16 + 56+ lymphocyte phenotypes, whereas absolute numbers of CD4+ lymphocytes and CD19+ cells increased. T-cell activation markers HLA-DR and IL-2R alpha were downregulated. rHuIL-10 did not influence HLA-DR expression on monocytes. ICAM-1 modulation on monocytes and neutrophils was mild and inconsistent. Fc gamma RI expression was upregulated on both neutrophils and monocytes. CONCLUSIONS: These data indicate that the immunosuppressive effects of rHuIL-10 treatment are partly different from its in vitro observed actions. The increase of the cytotoxicity-mediating Fc gamma RI points to potential immunostimulating properties of this cytokine.

Adult↗
PubMed1999

A role for IL-16 in the cross-talk between dendritic cells and T cells.

Dendritic cells (DCs) in the periphery capture and process Ags, migrate to lymphoid organs, and initiate immune responses in T cells. IL-16, the soluble ligand for CD4, is a potent chemoattractant for CD4+ T cells, eosinophils, and monocytes and is mainly derived from activated T cells. Because migration is a fundamental property of DCs, we asked whether IL-16 induces chemotaxis in DCs and whether DCs are a source of IL-16. DCs were generated by culture of monocytes in IL-4 and GM-CSF for 6 days and subsequently highly purified employing magnetic beads. Migration was assayed by nitrocellulose and polycarbonate filter-based assays, and distinction of chemotaxis and chemokinesis was performed by a checkerboard analysis. Messenger RNA and protein data revealed constitutive expression and release of IL-16 by day-6 DCs. Gradients of rIL-16 induced a chemotactic response of DCs. Furthermore, the chemotactic activity of DC supernatant toward DCs themselves and T cells was mainly due to IL-16, because the addition of neutralizing Abs completely abrogated the migratory response. However, after induction of maturation by the addition of TNF-alpha and PGE2 DCs, neither expressed IL-16 mRNA nor produced IL-16 protein. We conclude that IL-16 may play a role in the trafficking of DCs and may be a major chemotactic signal from DCs toward themselves and toward T cells.

Cell Communication↗
PubMed1999

Interferon alpha augments activation-induced T cell death by upregulation of Fas (CD95/APO-1) and Fas ligand expression.

Interferon alpha (IFN-alpha) plays a prominent role in the therapy of a variety of diseases. The Fas/FasL system is crucial for the cytotoxic function and the peripheral elimination of activated T lymphocytes (ATC) by a mechanism referred to as activation-induced cell death (AICD). Recent studies suggest a link between IFN-alpha, the 2', 5'- oligoadenylate system and apoptosis. We therefore asked whether IFN-alpha is able to regulate the Fas/FasL pathway and thereby affects AICD. Peripheral blood mononuclear cells (PBMC), purified T cells and ATC of healthy volunteers were stimulated with various agents and the influence of IFN-alpha on Fas/FasL was assessed by mRNA and protein studies. The proportion of ATC undergoing AICD or anti-Fas-induced apoptosis was determined by FITC-annexin V staining and propidium iodide uptake. IFN-alpha upregulated mRNA expression of Fas and FasL in activated PBMC. Furthermore the concentration of the soluble form of FasL (sFasL) was increased in PBMC and T cells co-stimulated with IFN-alpha and various agents, whereas Fas surface expression was enhanced by IFN-alpha alone. IFN-alpha enhanced apoptosis induced by anti-Fas antibody and augmented AICD via the Fas/FasL pathway. IFN-alpha-regulated AICD may contribute to lymphopenia observed during IFN-alpha therapy. Our data further support that IFN-alpha is a multifunctional cytokine with profound effects on the immune cascades.

Annexin A5↗
PubMed1999

Mediator-dependent effects of pentoxifylline on endothelium for transmigration of neutrophils.

In the present study, we investigated the effects of the anti-inflammatory drug pentoxifylline (PTX) on activation of endothelial cells for enhanced adhesion and transmigration of neutrophils by lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1) and granulocyte colony-stimulating factor (G-CSF). To evaluate the mechanism by which PTX exerts its effect, human umbilical vein endothelial cells (HUVEC) were pretreated with theophylline, 2'-O-dibutyryl-3', 5'-cyclic adenosine monophosphate (db cAMP), and 3-isobutyl-1-methylxanthine, respectively, prior to stimulation. Pretreatment of HUVEC with PTX significantly antagonized TNF-, IL-1-, and G-CSF-activated transmigration of neutrophils. Additive stimulatory effects of PTX were seen with LPS. With the exception of theophylline, all other test cAMP-raising agents stimulated transmigration in similar fashion to PTX. Upon stimulation with TNF or LPS, HUVEC produced IL-8 and PTX affected this process in opposing fashions, with inhibition of the effects of TNF and augmentation of those of LPS. These results demonstrate that PTX differentially affects mediator-induced activation of HUVEC. The present IL-8 dependent and cAMP-regulated augmentation of LPS-induced stimulation of transmigration is the first description of an additive effect of PTX with a pro-inflammatory agent.

1-Methyl-3-isobutylxanthine↗