Biomedical subjects

V Hummel

Publications and source records attributed to V Hummel.

5 recordsLinked to original sources

PubMed2003

Modulation of cytokine mRNA expression by brain-derived neurotrophic factor and nerve growth factor in human immune cells.

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) exert various effects on immune cells. Here we studied, whether they influence the cytokine expression pattern in peripheral blood mononuclear cells (PBMCs) or antigen specific T-cells. In PBMCs BDNF and NGF had interindividually variable effects on T helper cell type (Th)1- and Th2-cytokines. However, there was a high correlation between the modulating properties of these neurotrophins (r=0.97) concerning the expression of interleukin (IL) 4, transforming growth factor-beta and tumour necrosis factor-alpha mRNA at a concentration of 100 ng/ml. In myelin basic protein-specific T-cell lines BDNF and NGF increased interferon -gamma mRNA to a moderate extent, but not IL4. No major effects were detected at the cytokine protein level. In conclusion, our results suggest a partial effect of neurotrophins on immune cells, which may be modified by other signals.

Brain-Derived Neurotrophic Factor↗

PubMed2002

Human cerebral endothelial cells are a potential source for bioactive BDNF.

Inflammatory stimuli within the central nervous system may not only induce tissue damage but may also convey neuroprotection. It has been shown that brain derived neurotrophic factor (BDNF) is a neuroprotective candidate. Here we show that BDNF is constitutively expressed in cultured human cerebral endothelial cells (HCEC) and can further be upregulated under proinflammatory conditions. TNF-alpha treatment resulted in an increase in BDNF mRNA expression and protein levels were significantly elevated after 72 h (69+/-33%, P<0.01). Using functional assays it was demonstrated that BDNF produced by HCEC is bioactive and supports motoneuron survival. In contrast, BDNF expression was reduced by TNF-alpha in human umbilical vein endothelial cells (HUVEC). We conclude that HCEC likely to contribute to neuronal survival under physiological and inflammatory conditions.

Brain-Derived Neurotrophic Factor↗

PubMed2001

Effects of oncostatin M on human cerebral endothelial cells and expression in inflammatory brain lesions.

Oncostatin M (OSM) is a member of the interleukin (IL)-6 cytokine family and modulates inflammatory responses. Here we investigated the role of OSM as an immunoregulatory factor for human cerebral endothelial cells (HCEC). Using RT-PCR we detected transcripts of the receptor components involved in OSM signaling, gp130, OSM receptor (OSMR)-beta, and leukemia inhibitory factor receptor (LIFR), in HCEC. A parallel FACS analysis revealed surface expression of gp130 and OSMR-beta, but not of LIFR on these cells. Functionally, OSM upregulated intercellular adhesion molecule-1, but did not induce vascular cell adhesion molecule-1 in HCEC. Further, OSM upregulated IL-6 and monocyte chemoattractant protein (MCP)-1, whereas IL-8 was unaffected. Combined application of tumor necrosis factor (TNF)-alpha and OSM synergistically enhanced IL-6 and MCP-1 production, but downregulated TNF-alpha-induced IL-8. As OSM regulated molecules relevant in inflammatory brain diseases, we investigated its expression in normal and pathological human brains. OSM was detected by immunohistochemistry in brains from multiple sclerosis patients in microglia, reactive astrocytes, and infiltrating leukocytes, whereas in normal brains and noninflammatory neurological diseases. immunoreactivity was absent from the parenchyma. These data suggest that immunoregulatory functions in human cerebral endothelial cells may be a mechanism by which OSM participates in the pathophysiology of inflammatory brain disease.

Adult↗

PubMed2001

Production of MMPs in human cerebral endothelial cells and their role in shedding adhesion molecules.

Matrix metalloproteinases (MMPs) are Zn2+-endopeptidases that seem to play an important role in chronic inflammatory diseases of the central nervous system by disrupting the blood-brain barrier (BBB) and mediating the destruction of myelin components. We therefore investigated the influence of the pro-inflammatory cytokine TNF-alpha. on the expression and activation of several MMPs in human cerebral endothelial cells (HCEC). HCEC constitutively express MMP-2 and MMP-3 mRNA, but only MMP-3 is upregulated on mRNA and protein level after TNF-alpha stimulation. MMP-9 and MMP-12 mRNA could only be detected under inflammatory conditions. Furthermore, MMPs are involved in shedding of cell surface molecules. We therefore investigated the influence of MMPs on the release of soluble adhesion molecules using marimastat, a specific broad-spectrum MMP inhibitor and other protease inhibitors like aprotinin or leupeptin. Only marimastat inhibited the TNF-alpha mediated release of sVCAM-1 in the supernatants of HCEC. Western blot results of culture supernatants supported the time dependent release of the complete extracellular portion of the VCAM-1 molecule. These data suggest that MMPs produced by HCEC are actively involved in the shedding of soluble adhesion molecules at the BBB.

Alternative Splicing↗

PubMed2000

Cytokine-induced modulation of cellular adhesion to human cerebral endothelial cells is mediated by soluble vascular cell adhesion molecule-1.

Tumour necrosis factor-alpha ( TNF-alpha) has been proposed as one of the key mediators of inflammatory diseases of the CNS such as multiple sclerosis. It has been shown to induce the expression of adhesion molecules which is a prerequisite for the transmigration of immune cells through the blood-brain barrier. We therefore investigated the role of TNF-alpha in the expression and release of vascular cell adhesion molecule-1 (VCAM-1) in cultures of human cerebral endothelial cells (HCEC) in comparison with peripheral blood mononuclear cells (PBMC). A time- and dose-dependent expression of VCAM-1 and release of soluble VCAM-1 was detected in HCEC but not PBMC. TNF-alpha-induced release of soluble VCAM-1 was further increased by cotreatment with interferon-beta (IFN-beta), while IFN-beta alone did not affect VCAM-1 expression or the release of soluble VCAM-1. In addition, we observed that preincubation of PBMC with soluble VCAM-1 completely blocked their adhesion to HCEC. In conclusion, the proinflammatory effect of TNF-alpha on HCEC, which involves the induction of VCAM-1 expression and cellular adhesion, is followed by the consecutive effects of soluble VCAM-1 release in blocking adhesion and downregulating further cellular infiltration. Increasing soluble VCAM-1 release during active inflammation could be another mechanism by which IFN-beta treatment exerts protective effects in multiple sclerosis patients.

Antibodies, Monoclonal↗