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U Otten

Publications and source records attributed to U Otten.

At least 37 records · Page 2Linked to original sources
PubMed1999

Neural activities of IL-6-type cytokines often depend on soluble cytokine receptors.

Cytokines of the interleukin-6 (IL-6) family participate in regulatory and inflammatory processes within the nervous system. IL-6, ciliary neurotrophic factor (CNTF) and IL-11 act via specific membrane receptors which, together with their ligands, associate with signal-transducing receptor subunits thereby initiating cytoplasmic signalling. Cells which only express signal-transducing receptor subunits but no ligand binding subunits for IL-6, CNTF and IL-11 are refractory to these cytokines. An unusual feature of the IL-6 cytokine family is that the soluble forms of the ligand binding receptor subunits generated by one cell type in complex with their ligands can directly stimulate the signal-transducing receptor subunits on different cell types which lack ligand binding receptor subunits. This process has been named transsignalling. This article focuses on the importance of transsignalling events in neuronal differentiation and survival responses.

Animals↗
PubMed1998

Sympathetic neurons can produce and respond to interleukin 6.

Neuronal expression of cytokines is an area of active investigation in the contexts of development, disease, and normal neural function. Although cultured rat sympathetic neurons respond very weakly to exogenous interleukin 6 (IL-6), we find that addition of soluble IL-6 receptor (sIL-6R) and IL-6 enhances neuronal survival in the absence of nerve growth factor. Neutralizing monoclonal antibodies against IL-6 block these effects. Addition of IL-6 and sIL-6R also induces a subset of neuropeptide and transmitter synthetic enzyme mRNAs identical to that demonstrated for leukemia inhibitory factor, ciliary neurotrophic factor, and oncostatin M. Both of these effects are duplicated by addition of a highly active fusion protein of sIL-6R and IL-6, covalently linked by a flexible peptide chain, which is designated H-IL-6. In addition, we show that sympathetic neurons produce IL-6. In situ hybridization indicates a neuronal localization of IL-6 mRNA in superior cervical ganglia, and bioactive IL-6 protein is detected in ganglion culture supernatants. Interestingly, the IL-6 produced by sympathetic neurons does not lead to survival of these cells in culture unless sIL-6R is added. Thus, sympathetic neurons can produce IL-6 and may respond to it in an autocrine/paracrine manner if sIL-6R is present. Moreover, the prior findings of sIL-6R in serum and inflammatory fluids now have added interest in the context of neuro-immune interactions.

3T3 Cells↗
PubMed1998

Decreased trkA neurotrophin receptor expression in the parietal cortex of patients with Alzheimer's disease.

The cholinergic neurons of the basal forebrain system are sensitive to nerve growth factor (NGF), a member of the neurotrophin gene family. Since the cholinergic system is affected early in the course of Alzheimer's disease (AD), it was hypothesized that a deficit in NGF, e.g. reduced neurotrophin uptake by specific receptors, may play a role in neuronal cell death in AD. We quantitated mRNA levels of neurotrophins (NGF, BDNF, NT-3, NT-4/5) and their receptors (trkA, trkB, trkC, p75) in AD postmortem parietal cortex (n = 16) and cerebellum (n = 11). We applied highly sensitive reverse transcription-polymerase chain reaction (RT-PCR) in rapid autopsy derived brain tissue (mean postmortem delay 147+/-96 min., n = 53) to minimize postmortem mRNA variations. In the AD parietal cortex trkA mRNA levels were more than two times lower as compared to controls (n = 16, mean+/-SEM 0.26+/-0.07 units/S12, range, 0-1.78, and n = 11, 0.59+/-0.10 units/S12, range, 0.17-1.10, respectively, P = 0.015). TrkA mRNA levels did not appear to be altered in the AD cerebellum as compared to normal human cerebellum. NGF, BDNF, NT-3, NT-4/5, as well as trkB, trkC and p75 mRNA levels were unchanged in AD parietal cortex and cerebellum as compared to controls. This finding suggests that a reduced expression of the trkA receptor may contribute to impaired NGF-trkA signalling and a reduced transport of NGF in cholinergic neurons. These results reveal a central specific role of the high affinity NGF receptor during neurodegeneration in AD.

Aged↗
PubMed1998

NF-kappaB modulates lipopolysaccharide-induced microglial nerve growth factor expression.

Microglia/brain macrophages activated in response to injury, infection, or inflammation of the central nervous system (CNS) mediate both neurotoxic and neurotrophic activities. Although the cytotoxic effects of microglia have been analyzed in detail, little is known about the signaling pathways involved in microglial neurotrophin expression. Using purified rat microglial cell cultures, the effects of inflammatory agents such as lipopolysaccharide (LPS) on microglial nerve growth factor (NGF) expression were studied. Application of LPS (0.1-100 ng/ml) induced a rapid (2-4 h), dose-dependent increase in NGF mRNA expression followed by enhanced release of NGF protein within 24 h. To determine whether the transcription factor NF-kappaB, known to be stimulated in activated microglia, is involved in inflammatory mediator-induced NGF expression, we used the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC). Addition of PDTC (100 microM) to microglia completely abolished LPS-induced NGF synthesis, suggesting a key role for NF-kappaB in microglial NGF expression by inflammatory mediators. In conclusion, NF-kappaB-controlled NGF expression by activated microglia appears to contribute to the cross-talk between the immune and nervous systems during inflammation in the CNS.

Animals↗
PubMed1998

Modulation of mRNA expression of the neurotrophins of the nerve growth factor family and their receptors in the septum and hippocampus of rats after transient postnatal thyroxine treatment. I. Expression of nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin 4 mRNA.

Early postnatal application of thyroid hormones to rats results in morphological changes in septum and hippocampus. Modulation in the expression of either neurotrophins and/or their receptors is postulated to be responsible for these effects. In the present study we tested whether thyroxine administration leads to changes in the expression of neurotrophins of the nerve growth factor (NGF) family. Newborn rats were treated daily with subcutaneous injections of thyroxine until postnatal day (P) 12 at maximum. The pups were killed at defined intervals from P2 to 21. The septal area and the hippocampi were analyzed using the reverse transcriptase-PCR method for quantitation of NGF, brain-derived neurotrophic factor (BDNF), NT-3, and NT-4 messenger RNA (mRNA) levels. In hippocampus of hyperthyroid rats, as compared to controls, we found higher levels of BDNF and NT-3 mRNA over the total investigation period, whereas in the septum a thyroxine-dependent increase in NT-3 mRNA expression was observed. In addition, significant thyroxine-induced effects were found for all variables (except for NGF in the septum) at particular postnatal days. From these data we conclude that modulation of neurotrophin expression is a possible mechanism for the morphological modifications within the hippocampal mossy fiber system and the septohippocampal cholinergic system.

Animals↗
PubMed1998

Axotomy-induced c-JUN expression in young medial septal neurons is regulated by nerve growth factor.

In the present study we investigated the axotomy-induced expression of the proto-oncogene c-jun in young rat medial septal neurons and its regulation by nerve growth factor. First, medial septal neurons were retrogradely labelled by Fast Blue injection into the hippocampus at postnatal day 1 (P1). Rats of different developmental ages (P6, P9, P14, P21, P28 and P42) were then subjected to bilateral fimbria-fornix transection resulting in the axotomy of septohippocampal projection neurons. After the lesion, c-JUN immunoreactivity was observed in the nuclei of axotomized medial septal neurons of all stages examined, suggesting that c-JUN induction is an age-independent feature of axotomized medial septal neurons. Double immunolabelling for choline acetyltransferase and c-JUN or parvalbumin and c-JUN, respectively, revealed that both cholinergic and GABAergic septohippocampal projection neurons express c-JUN after axotomy. In addition, a co-localization of immunostaining for c-JUN and the neuropeptide galanin was found after lesion, as both proteins were induced in the same medial septal neurons following fimbria-fornix transection. Next, the regulation of c-JUN expression in axotomized medial septal neurons was studied in organotypic cultures of the medial septum. Axotomized medial septal neurons in culture did not express c-JUN in contrast to the in vivo situation. With the concept that nerve growth factor suppresses c-JUN expression, slice cultures of the medial septum were treated with antibodies against nerve growth factor. This treatment caused a dose-dependent increase in c-JUN-positive cells in these slice cultures. Simultaneous addition of nerve growth factor and antibodies against nerve growth factor resulted in the reversal of this effect. These data suggest an age-independent induction of c-JUN in axotomized medial septal neurons and its regulation by nerve growth factor.

Acetylcholine↗
PubMed1998

Inflammatory signals induce neurotrophin expression in human microglial cells.

Inflammatory processes involving reactive microglia, e.g., those associated with beta-amyloid containing neuritic and core plaques in Alzheimer's disease, appear to contribute to neuronal degeneration in the CNS. The fact that increased nerve growth factor (NGF) protein levels were found throughout brains of Alzheimer's disease patients led us to investigate neurotrophin synthesis in a human microglial cell line showing typical properties of human microglial cells, including expression of neurotrophins such as NGF, as well as the NGF receptor trkA and the low-affinity neurotrophin receptor p75. We found that the cytokines interleukin-1beta and tumor necrosis factor-alpha synergistically stimulate microglial NGF transcription and protein release. Moreover, exposure of microglial cells to complement factor C3a induces NGF expression. To assess the role of the transcription factor nuclear factor-kappaB (NF-kappaB) in inflammatory mediator-induced microglial NGF expression, the effect of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) was analyzed. In the presence of PDTC, a dose-dependent inhibition of cytokine-activated NGF expression occurred. In contrast, the C3a-dependent stimulation of NGF synthesis was not influenced by PDTC. In addition, microglial neurotoxicity-mediating beta-amyloid peptides A beta(1-40) and A beta(1-42) failed to alter NGF synthesis, whereas A beta(25-35) specifically induced NF-kappaB-dependent microglial NGF expression. In conclusion, inflammatory signals (cytokines and complement factors), as well as A beta(25-35), are potent stimulators of human microglial NGF synthesis involving NF-kappaB-dependent and -independent mechanisms. Microglial secretion of neurotrophins appears to be involved in early processes of neuronal regeneration.

Amyloid beta-Peptides↗
PubMed1997

Interleukin-6 (IL-6) and soluble forms of IL-6 receptors are not altered in cerebrospinal fluid of Alzheimer's disease patients.

We quantitated interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and soluble form of the IL-6 signal-transducing protein gp130 (sgp130) in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) (n = 17) and control subjects (n = 18) using sensitive enzyme-linked immunosorbent assays (ELISA). Our results show that none of the parameters examined was significantly different in CSF of AD patients as compared to control age-matched non-demented patients. We conclude that CSF levels of IL-6 and their soluble receptors do not necessarily reflect local changes of the IL-6 system that has been shown to be involved in neurodegenerative events occurring in AD. Levels of sgp130 are substantially high (approximately 100 ng/ml) in the CSF of all individuals probably representing a high antagonistic potential.

Aged↗
PubMed1997

Nerve growth factor (NGF) expression in rat microglia is induced by adenosine A2a-receptors.

Microglial response to stimuli is characterized by secretion of both neurotoxic and neurotrophic factors. Various adenosine receptor agonists stimulated the production of nerve growth factor (NGF) in microglia. Using reverse transcription-polymerase chain reaction (RT-PCR)- and ELISA-techniques, we show that the mixed A1- and A2-agonist 5'-(N-ethylcarboxamido)-adenosine (NECA) induces an increase in NGF mRNA expression and NGF protein release. Whereas the A1-specific agonist cyclopentyladenosine (CPA) only minimally affected NGF release, the A2a-specific agonist CGS-21680 triggered the greatest increase in microglial NGF synthesis. Analyzing the selective antagonist (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (EXIP), as well as modulators of the cyclic AMP (cAMP) pathway, we identified an adenosine A2a-receptor-sensitive, cAMP-mediated mechanism of microglial NGF synthesis. Our results indicate that A2a-adenosine receptors modulate microglial neurotrophin expression and release.

Adenosine↗
PubMed1997

Possible role of cytochrome P450 in inactivation of testosterone in immortalized hippocampal neurons.

The hippocampus as part of the limbic system is sensitive to gonadal hormones. The time-dependent expression of steroid receptors and the testosterone converting enzyme aromatase (CYP19) is well studied. In contrast, little is known about other cytochrome P450 enzymes in hippocampus which inactivate the gonadal hormones. For investigation of the total cytochrome P450 content and the expression of testosterone degrading CYP2B10 we used embryonic (E18) in comparison to postnatal (P21) immortalized hippocampal neurons. These embryonic neurons were demonstrated to react to hormones according a 'critical period' of sexual differentiation: testosterone treatment (1 microM to 5 microM in the culture medium) resulted in a decrease of beta-tubulin, as showed by immunocytochemistry and Western blotting. Measurements with reduced CO-difference spectrum elucidated that the P450 concentration in the embryonic neurons (10.2 pmol/mg protein; S.D. +/- 1.9) was twice as high as in the postnatal ones (5.2 pmol/mg protein; S.D. +/- 1.0). Correspondingly, a high value of the mitochondrial subfraction of approx. 141 pmol P450/mg protein was found in the embryonic neurons relative to the mitochondrial value of 37.7 pmol P450/mg protein in the postnatal neurons. Our results suggest a differential expression of cytochrome P450 during development. CYP2B10 was proved by electron microscopy and hormone degrading activity.

Age Factors↗
PubMed1997

Expression of GABA(A) receptors by reactive astrocytes in explant and primary cultures of rat CNS.

The presence of GABA(A)-receptors on astrocytes was studied in explant and primary cultures of rat cerebellum, hippocampus and spinal cord by means of immunohistochemistry. For these studies we have used the monoclonal antibody bd 17 against the beta2- and beta3-subunits of GABA(A)-receptor. In explant cultures many neurones were intensely stained with the GABA(A)-receptor antibody whereas adjacent astrocytes revealed little or no immunoreactivity. In the far outgrowth zone of explant culture, however, many immunostained astrocytes were observed. In primary astrocyte cultures, only a few cells were stained by the antibody. Astrocytes which became reactive after producing an artificial scar or after addition of certain compounds such as dibutyryl cyclic AMP, interleukin-6, basic fibroblast growth factor and kainic acid, also revealed GABA(A)-receptor immunoreactivity. Furthermore, these astrocytes were intensely stained for glial fibrillary acidic protein and vimentin. From our studies we conclude that only a sub-population of normal astrocytes are immunopositive for the GABA(A)-receptor antibody whereas astrocytes which become reactive following injury of the tissue or after addition of dibutyryl cyclic AMP, the cytokine interleukin-6, fibroblast growth factor or the neurotoxin kainic acid express GABA(A)-sites.

Animals↗
PubMed1997

Activation of gp130 by IL-6/soluble IL-6 receptor induces neuronal differentiation.

Interleukin-6 (IL-6) on target cells binds to the specific IL-6 receptor (IL-6R) and subsequently induces homodimerization of the signal-transducing protein gp130. Cells which express gp130 but no IL-6R and which therefore do not respond to IL-6 can be stimulated by the complex of IL-6 and soluble IL-6R (slL-6R). Here we show that on rat pheochromocytoma cells (PC12), the combination of IL-6 and slL-6R but not IL-6 alone induces expression of c-fos, GAP-43 and neuron-specific enolase followed by neuron-specific differentiation and formation of a neuronal network. The differentiation was dose-and time-dependent and followed the same kinetics as nerve-growth factor (NGF)-induced differentiation. The responses of PC12 cells to IL-6/sIL-6R and NGF were additive, suggesting independent signaling pathways. We demonstrate that activation of gp130 generates a neuronal differentiation signal that is equivalent to and independent of trk/NGF receptor tyrosine kinase. Interestingly, the failure of IL-6 to induce differentiation of PC12 cells is not due to lack of surface expression of IL-6R as IL-6 alone triggered expression of GAP-43 mRNA and protein. We hypothesize that PC12 cells express more gp130 than IL-6R and that the extent of activated gp130 molecules determines the quality of the response.

Animals↗
PubMed1997

[Vaccination project for vocational students].

As part of a North-Rhine-Westphalian state project the district of Unna developed a vaccination programme for continuation schools in 1996. The reason for this programme realized for the first time in a vocational school, was a considerable lack of protection by vaccination in ninth year classes. The present results from the first vocational school show a significant lack of standard vaccination as well as boosters. To improve the current situation it will be necessary to authorize and enable the Public Health Services to carry out even more standard and indication vaccinations at secondary and vocational schools as well as at institutions for the handicapped.

Adolescent↗
PubMed1996

Postnatal expression of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) mRNAs in rat sympathetic and sensory ganglia.

The postnatal expression of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) mRNAs in superior cervical ganglia (SCG) and dorsal root ganglia (DRG) of normal rats were studied by using RT-PCR. IL-6 and IL-6R transcripts were found in both these peripheral nervous system (PNS) tissues and their expression was differentially regulated. In sensory ganglia, a strong upregulation (12-fold) of the IL-6R mRNA occurred between postnatal day 2 and day 20, staying at this elevated level until adulthood (day 70). During the same period the IL-6 mRNA increased to a lesser extent (3-fold). In SCG, both transcripts undergo only a minor induction (2-fold) during postnatal development. To identify the cellular source of IL-6 and its receptor mRNAs in both PNS tissues, a sensitive non-radioactive in situ hybridization technique was used. Both mRNAs could be localized predominantly in the neuronal cell bodies in the sympathetic and sensory ganglia. In addition, IL-6R mRNA positive cells were found located along the axon outside the DRG, and are likely to be Schwann cells. The same cells were negative for IL-6 mRNA. These findings support the concept of IL-6 as a regulator of neuronal survival and differentiation in the central and peripheral nervous system.

Age Factors↗
PubMed1996

Expression of interleukin-6 receptor (IL-6R) and gp130 mRNA in PC12 cells and sympathetic neurons: modulation by tumor necrosis factor alpha (TNF-alpha).

Recent findings indicate that IL-6, besides its various biological effects, also exerts neurotrophic and neuroprotective functions. Using the pheochromocytoma cell line PC12 and cultured primary sympathetic neurons, we investigated whether neurons express the IL-6 receptors, IL-6R and gp130, and how they might be regulated. For these studies we used RT-PCR and in situ hybridization. We provide here evidence for the expression of functional IL-6Rs in peripheral sympathetic neurons and PC12 cells. Furthermore we demonstrate that cytokines modulate the expression of IL-6R and gp130 mRNA. This modulation is much more pronounced in neuronally-differentiated PC12 cells than in undifferentiated cells. Among various cytokines tested, tumor necrosis factor alpha (TNF-alpha) turned out to be a major regulator of the IL-6R and gp130 mRNA expression. The induction was time- and dose-dependent for both genes. Maximal induction was reached within 16 h at a concentration of 0.1 nM TNF-alpha. The stimulatory effect of TNF-alpha on the IL-6R system was completely inhibited by the simultaneous addition of the glucocorticoid dexamethasone. In summary, our results show that sympathetic neurons and neuron-like differentiated PC12 cells express functional IL-6R and gp130, and that the expression of their mRNAs is modulated by cytokines. We suggest that cytokines such as IL-6 can modulate sympathetic neuron function.

Animals↗
PubMed1995

Modulatory role of platelet-derived growth factor on cytokine-induced nerve growth factor synthesis in rat glomerular mesangial cells.

Recent evidence indicates that cytokines are potent inducers of nerve growth factor (NGF) expression in peripheral tissues and in brain. Cultured rat glomerular mesangial cells respond to interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) by increased NGF synthesis. We found that co-stimulation of rat glomerular mesangial cells with platelet-derived growth factor (PGDF-BB) and IL-1 beta/TNF-alpha significantly augments the IL-1 beta/TNF-alpha-induced NGF mRNA levels and NGF synthesis. In contrast, preincubation with PDGF-BB drastically reduces NGF gene expression and NGF protein synthesis in response to IL-1 beta/TNF-alpha stimulation. Thus our results indicate that PDGF-BB is a potent modulator of cytokine-induced NGF expression; its precise action is critically depending on the time at which the PDGF receptor is activated.

Animals↗
PubMed1995

Expression of interleukin-6 (IL-6) and IL-6 receptor mRNAs in rat adrenal medulla.

Using in situ hybridization and reverse transcription combined with the polymerase chain reaction (RT-PCR) we have studied the expression and developmental regulation of interleukin-6 (IL-6) and its receptor mRNAs in rat adrenal medulla. Labeling for both transcripts was much more intense over the adrenal medulla than over cortical regions at postnatal day 70. Levels of mRNAs of both genes measured by RT-PCR increased from birth to adulthood. In vitro survival and neurite growth of chromaffin cells from early postnatal rats were not affected by IL-6. Even so, the presence and developmental regulation of IL-6 and its receptor are consistent with a possible auto- or paracrine role of IL-6 in rat adrenal medulla.

Adrenal Glands↗