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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of inflammatory disorders of the central nervous system (CNS) whereas the contribution of the major endogenous counter-regulators of MMPs, the tissue inhibitors of the matrix metalloproteinases (TIMPs), is unclear. We investigated the temporal and spatial expression patterns in the CNS of nine MMP genes and three TIMP genes in normal mice, in mice with EAE, and in transgenic mice with astrocyte (glial fibrillary acidic protein)-targeted expression of the cytokines interleukin-3 (macrophage/microglial demyelinating disease), interleukin-6 (neurodegenerative disease), or tumor necrosis factor-alpha (lymphocytic encephalomyelitis). In normal mice, the MMPs MT1-MMP, stromelysin 3, and gelatinase B were expressed at low levels, whereas high expression of TIMP-2 and TIMP-3 was observed predominantly in neurons and in the choroid plexus, respectively. In EAE and the transgenic mice, significant induction or up-regulation of various MMP genes was observed, the pattern of which was somewhat specific for each of the models, and there was significant induction of TIMP-1. In situ localization experiments revealed a dichotomy between MMP expression that was restricted to leukocytes and possibly microglia within inflammatory lesions and TIMP-1 expression that was observed in activated astrocytes circumscribing the lesions. These findings demonstrate specific spatial and temporal regulation in the expression of individual MMP and TIMP genes in the CNS in normal and inflammatory states. The distinct localization of TIMP-1 and MMP expression during CNS inflammation suggests a dynamic state in which the interplay between these gene products may determine both the size and resolution of the destructive inflammatory focus.
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PMID:Differential expression of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mouse central nervous system in normal and inflammatory states. 950 15

Transgenic mice, named GFAP-IL6, that express interleukin-6 in astrocytes in the central nervous system (CNS) have a constitutive blood-brain barrier (BBB) defect and develop a progressive neurodegenerative disease. Based on ultrastructural observations showing electron-dense pigment in the brain of the GFAP-IL6 mice, we hypothesized that iron metabolism was altered in the brains of these animals. Enhanced histochemical methods revealed abnormal iron deposition in the cerebellum from 1 month of age that worsened with progression of the disease. Immunohistochemical analysis of iron-binding proteins (IBP) showed increased ferritin immunoreactivity and a decreased signal from the transferrin receptor in symptomatic animals. Atomic absorption spectroscopy revealed a 40% increase of total iron concentration in the cerebellum at the symptomatic stage. In order to obtain evidence that accumulation of this oxidizing metal was toxic, we looked for the presence of oxidative damage. Using the MAL-2 antibody, extensive lipid peroxidation (LP) was detected in the neocortex and the cerebellum in symptomatic animals. Ultrastructural analysis indicated lipofuscin deposition at the sites of neuro-axonal degeneration and abnormal iron deposition. These results suggest that the IL6-induced BBB defect precipitates iron accumulation in the GFAP-IL6 mouse brain and that subsequent IBP regulation mediates protective responses. As these defenses become overwhelmed, the iron overload seems to promote LP, which may contribute to the neurodegeneration that ensues. This transgenic mouse model of IL6-mediated neurodegeneration provides a unique opportunity to examine several aspects of iron metabolism in the brain, including its entry at the site of the BBB, its distribution through the IBP, and its mechanisms of toxicity.
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PMID:Abnormal iron deposition associated with lipid peroxidation in transgenic mice expressing interleukin-6 in the brain. 960 Feb 19

Cytokines are powerful mediators of biologic responses in the CNS and may contribute to cellular injury in pathophysiologic states. In order to better understand the actions of cytokines in the intact mammalian CNS, a transgenic approach was employed that targeted the expression of different cytokines to astrocytes in mice. Fusion gene constructs consisting of a GFAP expression vector into which was inserted the DNA encoding the cytokines interleukin-6 (IL-6), IL-3, or TNF-alpha were used to generate transgenic mice. Expression of the transgene-encoded cytokines in astrocytes was confirmed at both the RNA and protein levels. Transgenic mice were subject to multilevel analysis to determine the extent of structural and functional CNS alterations. Transgenic mice exhibited distinct adult-onset, chronic-progressive neurological disorders that correlated with the level and anatomic distribution of transgene-encoded cytokine expression. The principal findings were neurodegeneration and cognitive decline due to IL-6 expression, macrophage/microglial-mediated primary demyelination with motor disease resulting from IL-3 expression, and lymphocytic meningoencephalomyelitis with paralysis induced by TNF-alpha expression. These transgenic models (1) indicate that expression of cytokines per se in the intact CNS is pathogenic, with cytokine-specific neural cell injury leading to unique functional deficits; (2) recapitulate many of the structural and functional changes seen in human inflammatory neurological disorders; (3) provide a valuable tool for advancing our understanding of the CNS pathobiology of cytokines; and (4) offer a unique resource for the development and testing of therapies aimed at abrogating the harmful actions of these important mediators.
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PMID:Structural and functional impact of the transgenic expression of cytokines in the CNS. 962 40

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.
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PMID:Expression of GABA(A) receptors by reactive astrocytes in explant and primary cultures of rat CNS. 964 26

The effect of interleukin-6 (IL-6) on metallothionein-I (MT-I) and MT-III expression in the brain has been studied in transgenic mice expressing IL-6 under the regulatory control of the glial fibrillary acidic protein gene promoter (GFAP-IL6 mice), which develop chronic progressive neurodegenerative disease. In situ hybridization analysis revealed that GFAP-IL6 (G16-low expressor line, and G36-high expressor line) mice had strongly increased MT-I mRNA levels in the cerebellum (Purkinje and granular layers of the cerebellar cortex and basal nuclei) and, to a lesser degree, in thalamus (only G36 line) and hypothalamus, whereas no significant alterations were observed in other brain areas studied. Microautoradiography and immunocytochemistry studies suggest that the MT-I expression is predominantly localized to astrocytes throughout the cerebrum and especially in Bergman glia in the cerebellum. However, a significant expression was also observed in microglia of the GFAP-IL6 mice. MT-III expression was significantly increased in the Purkinje cell layer and basal nuclei of the cerebellum, which was confirmed by Northern blot analysis of poly(A)+ mRNA and by ELISA of the MT-III protein. In contrast, in the G36 but not G16 mice, transgene expression of IL-6 was associated with significantly decreased MT-III RNA levels in the dentate gyrus and CA3 pyramidal neuron layer of the hippocampus and, in both G36 and G16 mice, in the occipital but not frontal cortex and in ependymal cells. Thus, both the widely expressed MT-I isoform and the CNS specific MT-III isoform are significantly affected in a MT isoform- and CNS area-specific manner in the GFAP-IL6 mice, a chronic model of brain damage.
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PMID:Localization of metallothionein-I and -III expression in the CNS of transgenic mice with astrocyte-targeted expression of interleukin 6. 978 78

Increasing evidence supports an essential role for interleukin-6 (IL-6) in the development, differentiation, as well as de- and re-generation of neurons in the central nervous system (CNS). Both IL-6 and its specific receptor (IL-6R) are expressed on neurons and glial cells including astrocytes. In this study, we have analyzed the responses of primary rat astrocytes of various brain regions to IL-6 with respect to morphological changes and neurotrophin expression. Since IL-6 alone failed to initiate effects on astrocytes, we have examined whether the soluble IL-6R (sIL-6R) can modulate the responsiveness of to IL-6 in these cells. For this purpose, we used a highly active fusion protein of IL-6 and sIL-6R, which is designated Hyper-IL-6 (H-IL-6). We show that treatment of cultured astrocytes with Hyper-IL-6 promotes region-specific morphological changes of GFAP-positive astrocytes from typical stellate- to fibrous-like cells. In addition, we find that Hyper-IL-6 induces expression of neurotrophins (NTs) of the nerve growth factor (NGF)-family in a dose-dependent manner. Interestingly, astrocytes of various brain regions show differing patterns of cytokine-induced NT expression: NGF is maximally induced in cortex and hippocampus, NT-3 in hippocampus, and NT-4/5 in cortex and cerebellum. In summary, our results indicate that IL-6 in conjunction with sIL-6R regulates specific neurotrophin expression in astrocytes in a brain region dependent manner. Thus, the IL-6 system provides a local supply of neurotrophins that participate in diverse CNS functions such as protection of neurons from insults, neuronal survival, and neuro-immune responses.
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PMID:Role of interleukin-6 and soluble IL-6 receptor in region-specific induction of astrocytic differentiation and neurotrophin expression. 1034 Jul 60

gp130 is a signal-transducing receptor component used in common by the interleukin-6 (IL-6) family of hematopoietic and neurotrophic cytokines, including IL-6, IL-11, leukemia-inhibitory factor, ciliary neurotrophic factor, oncostatin-M, and cardiotrophin-1. We have examined in this study a role of gp130 in the nervous system by analyzing developmental cell death of several neuronal populations and the differentiation of astrocytes in gp130-deficient mice. A significant reduction was observed in the number of sensory neurons in L5 dorsal root ganglia and motoneurons in the facial nucleus, the nucleus ambiguus, and the lumbar spinal cord in gp130 -/- mice on embryonic day 18.5. On the other hand, no significant neuronal loss was detectable on day 14.5, suggesting a physiological role of gp130 in supporting newly generated neurons during the late phase of development when naturally occurring cell death takes place. Moreover, expression of an astrocyte marker, GFAP, was severely reduced in the brain of gp130 -/- mice. Our data demonstrate that gp130 expression is essential for survival of subgroups of differentiated motor and sensory neurons and for the differentiation of major populations of astrocytes in vivo.
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PMID:Developmental requirement of gp130 signaling in neuronal survival and astrocyte differentiation. 1037 52

It is well established that many cell types produce inflammatory cytokines and we were interested to see whether cells in the neurohypophysis had this ability. This study examines the effect of lipopolysaccharide (LPS) on cytokine production in cultured murine neural lobe (NL) cells. Cells were cultured from the neurohypophysis of mice not older than 5 days and the experiments were performed after 12 days in culture. The majority of cells in culture were immunoreactive for glial fibrillary acidic protein, indicating that the cells were pituicytes. Cytokines were measured in 24-hour samples using commercial ELISA kits. Cells growing in a medium free of endotoxin released 94.3 +/- 6.6 pg IL-6/NL/24 h (mean +/- SEM, n = 21). The release of interleukin-6 (IL-6) was reversible and increased concentration dependently with LPS in the concentration range of 0.1-1 ng/ml. The addition of 1 ng/ml LPS increased the IL-6 release 12-fold to a maximum value of 1,134 +/- 85.5 pg IL-6/NL/24 h (mean +/- SEM, n = 6). No trace of interleukin-1beta (IL-1beta) (<3 pg/NL/24 h) or tumor necrosis factor-alpha (<10 pg/NL/24 h) was detected after LPS stimulation. We examined the effect of dexamethasone (10(-6) M) and indomethacin (10(-4) M) on the release of IL-6 in submaximally stimulated cells. Dexamethasone inhibited the unstimulated and the LPS-stimulated release of IL-6 by 70 and 81%, respectively. Indomethacin had no influence on the release, and it is concluded that cyclooxygenase is not involved in the response. A close association exists between the membrane of the neurosecretory endings and the pituicytes in the neurohypophysis. This naturally raises the question as to whether IL-6 might reflect a physiological connection between the two cell types.
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PMID:Endotoxin-stimulated release of cytokines by cultured cells from the murine neurohypophysis: role of dexamethasone and indomethacin. 1047 51

Overproduction of proinflammatory cytokines in the brains of transgenic animals causes brain pathology. To investigate the relationship between brain cytokines and pathology in the brains of animals with adult-onset, pathophysiologically induced brain cytokine expression, we studied rats infected with the parasite Trypanosoma brucei. Several weeks after infection, in situ hybridization histochemistry showed a pattern of chronic overexpression of the mRNAs for proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha in the brains of the animals. Similar spatiotemporal inductions of mRNAs for inhibitory factor kappaBalpha and interleukin-1beta converting enzyme were found and quantified. The mRNAs for inducible nitric oxide synthase and interleukin-1 receptor antagonist were highly localized to the choroid plexus, which showed evidence of structural abnormalities associated with the parasites' presence there. The mRNAs for interleukin-6, interferon-gamma, and inducible cyclooxygenase showed restricted induction patterns. Another set of animals was processed for degeneration-induced silver staining, TdT-mediated dUTP-digoxigenin nick end-labeling (TUNEL) staining, glial fibrillary acidic protein (GFAP) immunohistochemistry, and several other histological markers. Apoptosis of scattered small cells and degeneration of certain nerve fibers was found in patterns spatially related to the cytokine mRNA patterns and to cerebrospinal fluid diffusion pathways. Furthermore, striking cytoarchitectonically defined clusters of degenerating non-neuronal cells, probably astrocytes, were found. The results reveal chronic overexpression of potentially cytotoxic cytokines in the brain and selective histopathology patterns in this natural disease model. J. Comp. Neurol. 414:114-130, 1999. Published 1999 Wiley-Liss, Inc.
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PMID:Chronic overexpression of proinflammatory cytokines and histopathology in the brains of rats infected with Trypanosoma brucei. 1049 82

Although interleukin-6 (IL-6) has various neuroprotective effects against cerebral ischemia, the topographic distribution and cellular source of IL-6 after cerebral ischemia remain unclear. In the current study, the localization of IL-6 protein was immunohistochemically examined in rats after 3.5, 12, 24, and 48 hours of reperfusion after 1.5 hours of middle cerebral artery occlusion. Middle cerebral artery occlusion was induced by the intraluminal suture method. The specificity of the anti-IL-6 antibody used in the current study was confirmed by Western blot analysis and an immunoabsorption test. To identify the cellular source, lectin histochemical study and immunohistochemical study with microtubule-associated protein-2, ED1, and glial fibrillary acidic protein also were carried out. The sham group did not show any clear IL-6 immunoreactivity. After 3.5 hours of reperfusion, IL-6 immunoreactivity was first detected on the reperfused side, and it was upregulated, especially in the periinfarct region, after 24 hours of reperfusion. Also, IL-6 was expressed after 3.5 hours of reperfusion in the contralateral cerebral cortex and bilateral hippocampi. Double staining showed that the cells containing IL-6 were neurons and round-type microglia, not astrocytes. The current findings suggest that IL-6 expression in ischemically threatened neurons and reactive microglia is closely associated with brain tissue neuroprotective mechanisms against cerebral ischemia.
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PMID:Temporal profile and cellular localization of interleukin-6 protein after focal cerebral ischemia in rats. 1056 72


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