UNIPROT:P05231 - FACTA Search

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

We examined the effects of interleukin-6 (IL-6) deficiency on brain inflammation and the accompanying bone marrow (BM) leukopoiesis and spleen immune reaction after systemic administration of a niacin antagonist, 6-aminonicotinamide (6-AN), which causes both astroglial degeneration/cell death in brain stem gray matter areas and BM toxicity. In both normal and genetically IL-6-deficient mice (IL-6 knockout (IL-6KO) mice), the extent of astroglial degeneration/cell death in the brain stem was similar as determined from disappearance of GFAP immunoreactivity. In 6-AN-injected normal mice reactive astrocytosis encircled gray matter areas containing astroglial degeneration/cell death, which were infiltrated by several macrophages and some T-lymphocytes. Reactive astrocytes and a few macrophages increased significantly the antioxidants metallothionein-I+II (MT-I+II) and moderately the MT-III isoform. In 6-AN-injected IL-6KO mice reactive astrocytosis and recruitment of macrophages and T-lymphocytes were clearly reduced, as were BM leukopoiesis and spleen immune reaction. Expression of MT-I+II was significantly reduced while MT-III was increased. Oxidative stress, as determined by measuring nitrated tyrosine and malondialdehyde, was increased by 6-AN to a greater extent in IL-6KO mice. The blood-brain barrier to albumin was only disrupted in 6-AN-injected normal mice, which likely is due to the substantial migration of blood-derived inflammatory cells into the CNS. The present results demonstrate that inflammation in CNS is clearly reduced during IL-6 deficiency and this effect is likely due to significant inhibition of BM leukopoiesis. We also show that IL-6 deficiency reduces the levels of neuroprotective antioxidants MT-I+II followed by an increased oxidative stress during CNS inflammation.
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PMID:IL-6 deficiency leads to reduced metallothionein-I+II expression and increased oxidative stress in the brain stem after 6-aminonicotinamide treatment. 1078 46

Oncostatin M (OSM) and other members of the interleukin-6 cytokines, like ciliary neurotrophic factor and leukemia inhibitory factor, can induce differentiation of glial cells. We have recently described that OSM inhibited the growth of human glioma cells in vitro and induced a cell morphology resembling that of mature astrocytes. Using the glioblastoma cell line 86HG39, we demonstrated that treatment of the glioma cells with OSM also leads to a differentiation of the malignant glioma cells as judged by a strong increase in glial fibrillary acidic protein expression. The differentiation and the growth inhibition were not significantly blocked by expression of a dominant-negative (dn) signal transducer and activator of transcription (Stat) 3 protein. OSM exerted a reduction in DNA synthesis even in the presence of a high expression level of dnStat3. Moreover, inhibition of the ras-raf-mitogen-activated protein kinase (MAPK) pathway by the MAPK kinase 1 inhibitor PD98059 resulted in a synergistic enhancement of the OSM effect, indicating that the activation of this pathway counteracts the activity of the cytokine.
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PMID:Oncostatin M-mediated growth inhibition of human glioblastoma cells does not depend on stat3 or on mitogen-activated protein kinase activation. 1093 78

Cytokines are important intercellular messengers involved in neuron-glia interactions and in the microglial-astroglial crosstalk, modulating the glial response to brain injury and the lesion outcome. In this study, excitotoxic lesions were induced by the injection of N-methyl-D-aspartate in postnatal day 9 rats, and the cytokines interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), tumour necrosis factor alpha (TNFalpha) and transforming growth factor beta 1 (TGF-beta1) analysed by ELISA and/or immunohistochemistry. Moreover, cytokine-expressing glial cells were identified by means of double labelling with glial fibrillary acidic protein or tomato lectin binding. Our results show that both neurons and glia were capable of cytokine expression following different patterns in the excitotoxically damaged area vs. the nondegenerating surrounding grey matter (SGM). Excitotoxically damaged neurons showed upregulation of IL-6 and downregulation of TNFalpha and TGF-beta1 before they degenerated. Moreover, in the SGM, an increased expression of neuronal IL-6, TNFalpha and TGF-beta1 was observed. A subpopulation of microglial cells, located in the SGM and showing IL-1beta and TNFalpha expression, were the earliest glial cells producing cytokines, at 2-10 h postinjection. Later on, cytokine-positive glial cells were found within the excitotoxically damaged area and the adjacent white matter: some reactive astrocytes expressed TNFalpha and IL-6, and microglia/macrophages showed mild IL-1beta and TGF-beta1. Finally, the expression of all cytokines was observed in the glial scar. As discussed, this pattern of cytokine production suggests their implication in the evolution of excitotoxic neuronal damage and the associated glial response.
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PMID:Neuronal, astroglial and microglial cytokine expression after an excitotoxic lesion in the immature rat brain. 1102 20

Proliferating astrocytes are frequently observed in diseased and injured brains. These newly generated astrocytes are necessary to reestablish the barriers that isolate the CNS from the rest of the body; however, they also create a matrix that inhibits regeneration and remyelination. Therefore, it is important to understand the mechanisms that enable a terminally differentiated astrocyte to reenter the cell cycle. Ciliary neurotrophic factor (CNTF), interleukin-6 (IL-6), transforming growth factor-alpha (TGF-alpha), and fibroblastic growth factor-2 (FGF-2) are four cytokines that are rapidly elevated in damaged neural tissue. These cytokines also have been implicated in glial scar formation. We sought to determine whether IL-6 and CNTF stimulate astroglial proliferation alone or in combination with other mitogens. Intraparenchymal CNTF modestly increased the number of proliferating cell nuclear antigen (PCNA) and glial fibrillary acidic protein (GFAP) double positive astrocytes when introduced by stereotactic injection into the adult rat brain. When applied directly to highly enriched rat forebrain astrocyte cultures, neither CNTF nor IL-6-stimulated DNA synthesis. Therefore, they are not astroglial mitogens. However, both cytokines synergized with epidermal growth factor (EGF), increasing its mitogenicity by approximately twofold. Astrocytes that had been "aged" for at least 3 weeks in vitro became refractory to EGF; however, when these "aged" astrocytes were pretreated with either IL-6 or CNTF for as little as 2 h, they became competent to reenter the cell cycle upon exposure to EGF. These data suggest that IL-6 type cytokines, likely by activating STAT family transcription factors, induce the expression of signaling molecules that endow resting astrocytes with the competence to respond to mitogens and to reenter the cell cycle.
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PMID:IL-6-type cytokines enhance epidermal growth factor-stimulated astrocyte proliferation. 1110 72

Because exogenous application of a number of cytokines and growth factors can alter synaptic properties, we sought to determine if endogenous cytokine expression is affected by neuronal activity. In addition, we examined whether cytokine expression is altered by the techniques used to stimulate and record from hippocampal neurons. Using semi-quantitative RNase protection and RT-PCR assays, we studied the expression of 18 cytokine, growth factor, and receptor genes in the hippocampus following the induction of Schaffer collateral-CA1 long-term potentiation (LTP). We found that various cytokines are dramatically induced following preparation of slices for in vitro recording and as a result of injury following acute electrode placement in vivo. These increases can be overcome in vivo, however, using permanent electrodes implanted three weeks prior to testing. Using this chronic preparation, we found that interleukin-6 (IL-6) mRNA was upregulated nearly 20-fold by LTP induction in vivo, marking the first demonstration of endogenous regulation of this cytokine in response to LTP. In situ hybridization for IL-6 revealed that upregulation is tightly localized near the site of stimulation and is detected only in non-neuronal cells, identified as GFAP+ astrocytes and GFAP- cells within proximal blood vessels. Coupled with previous results showing that exogenously applied IL-6 can prevent the induction of LTP, this finding suggests a mechanism by which the local release of a cytokine could regulate LTP at nearby sites.
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PMID:Cytokine responses to LTP induction in the rat hippocampus: a comparison of in vitro and in vivo techniques. 1111 99

Pituitary folliculostellate (FS) cells are usually located between the secretory cells in the anterior pituitary, and they produce many peptides that exert a paracrine effect on hormone-producing pituitary cells. Previous approaches have been unsuccessful in obtaining homogeneous populations of FS cells. We used a combination of immunostaining with S100 protein followed by laser capture microdissection (Immuno-LCM) to obtain purified populations of rat FS cells. These cells were analyzed along with a mouse FS cell line (TtT/GF) by RT-PCR for gene expression. RT-PCR analyses showed that both FS cell populations expressed the mRNAs for glial fibrillary acidic protein, S100 protein, transforming growth factor-beta1 (TGFbeta1), TGFbeta receptor, interleukin-6, leptin, leptin receptor, pituitary adenylate cyclase-activating polypeptide (PACAP), and PACAP receptors. Both FS cell populations were negative for PRL, GH, and POMC, supporting the homogeneity of the rat FS cell population. TGFbeta1, but not PACAP-38, treatment stimulated cell proliferation in both FS cell populations. TGFbeta1 increased leptin, but not interleukin-6, mRNA expression in rat FS cells. However, TGFbeta1 inhibited leptin RNA expression in the TtT/GF cell line, as shown by RT-PCR and Northern blot analysis. These results indicate that 1) homogeneous populations of FS cells can be prepared by Immuno-LCM; 2) TGFbeta1 stimulates the proliferation of normal rat FS cells and the TtT/GF cell line; and 3) the effects of TGFbeta1 to stimulate leptin mRNA expression in rat FS cells but inhibit leptin mRNA expression in TtT/GF cells probably reflect alterations in signal transduction in the TtT/GF cell line.
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PMID:Analysis of homogeneous populations of anterior pituitary folliculostellate cells by laser capture microdissection and reverse transcription-polymerase chain reaction. 1131 32

JAK-STAT is the major downstream signal pathway of interleukin-6 (IL-6) cytokine family and is regulated by Tyr705 phosphorylation of Stat3. The present study examined the extent and the localization of phosphorylated Stat3 protein in brain tissue after focal ischemia in rats. The localizations of unphosphorylated and phosphorylated Stat3 were immunohistochemically examined in rats after 0.5 to 168 h of reperfusion following 1.5 h of middle cerebral artery occlusion (MCAO), induced by the intraluminal suture method. Absolute phosphorylated Stat3 immunoreactive cell counts were made in the cerebral cortex (ischemic core, peri-ischemia region, and contralareral cortex) and lateral striatal regions on both the ischemic and the contralateral sides. Stat3 protein was localized diffusely in cortical and striatal neurons in the sham-operated animals. Although weak Stat3 staining was detected in damaged neurons in the ischemic region, activated microglia, astrocytes, and endothelial cells clearly expressed Stat3 in this region. On the other hand, the sham group showed no phosphorylated Stat3 immunoreactivity. Phosphorylated Stat3 immunoreactivity was first detected in neurons after 3.5 h of reperfusion in each cortical and striatal region. Thereafter, Stat3 phosphorylation was marked in neurons in the peri-infarct region, peaked at 24 h, and then gradually declined throughout the reperfusion period. Endothelial cells expressed phosphorylated Stat3 in the ischemic core at 48 h of reperfusion. To identify the cellular source of phosphorylated Stat3, lectin histochemical study and immunohistochemical study with anti-microtubule-associated proten-2 and anti-glial fibrillary acidic protein antibodies were carried out. Double-staining immunohistochemistry with these cellular makers revealed phosphorylated Stat3 to be present in neurons, but in neither astrocytes nor microglia/macrophages. These results were also confirmed be western blot analysis. The present results indicate that Stat3 activation occurs in neurons and endothelial cells only during post-ischemic reperfusion despite widespread expression of IL-6 cytokines.
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PMID:Phosphorylation of signal transducer and activator of transcription-3 (Stat3) after focal cerebral ischemia in rats. 1142 84

Microglial cells react early to a neurotoxic insult. However, the bioactive factors and the cell-cell interactions leading to microglial activation and finally to a neuroprotective or neurodegenerative outcome remain to be elucidated. Therefore, we analyzed the microglial reaction induced by methylmercury (MeHgCl) using cell cultures of different complexity. Isolated microglia were found to be directly activated by MeHgCl (10(-10) to 10(-6) M), as indicated by process retraction, enhanced lectin staining, and cluster formation. An association of MeHgCl-induced microglial clusters with astrocytes and neurons was observed in three-dimensional cultures. Close proximity was found between the clusters of lectin-stained microglia and astrocytes immunostained for glial fibrillary acidic protein (GFAP), which may facilitate interactions between astrocytes and reactive microglia. In contrast, immunoreactivity for microtubule-associated protein (MAP-2), a neuronal marker, was absent in the vicinity of the microglial clusters. Interactions between astrocytes and microglia were studied in cocultures treated for 10 days with MeHgCl. Interleukin-6 release was increased at 10(-7) M of MeHgCl, whereas it was decreased when each of these two cell types was cultured separately. Moreover, addition of IL-6 to three-dimensional brain cell cultures treated with 3 x 10(-7) M of MeHgCl prevented the decrease in immunostaining of the neuronal markers MAP-2 and neurofilament-M. IL-6 administered to three-dimensional cultures in the absence of MeHgCl caused astrogliosis, as indicated by increased GFAP immunoreactivity. Altogether, these results show that microglial cells are directly activated by MeHgCl and that the interaction between activated microglia and astrocytes can increase local IL-6 release, which may cause astrocyte reactivity and neuroprotection.
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PMID:Microglial reaction induced by noncytotoxic methylmercury treatment leads to neuroprotection via interactions with astrocytes and IL-6 release. 1174 82

The aim of this study was to localize various growth factors and cytokines in paragangliomas and pheochromocytomas in order to understand their possible autocrine or paracrine functions, and to compare sustentacular cells of the adrenal medulla with pituitary stellate cells. Thirteen resected tumors, 11 paragangliomas and 2 pheochromocytomas of the adrenal medulla, were studied. In addition, five surgically removed nontumorous adrenals and five nontumorous pituitaries were studied. Varying numbers of sustentacular cells were immunopositive for S-100 protein and in most instances for glial fibrillary acidic protein. Insulin-like growth factor-1 (IGF-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 were localized to both cell types in all cases, whereas epidermal growth factor (EGF) immunopositivity was noted in only three. In all tumors, leukemia inhibitory factor (LIF) was restricted to chief cells and EGF receptor to sustentacular cells. Nontumorous chief cells and sustentacular cells of adrenal medulla exhibited immunoreactivities similar to those of paragangliomas and pheochromocytomas. Secretory adenohypophysial cells displayed various immunoreactivities for all growth factors, receptors, and cytokines studied. Pituitary stellate cells were immunopositive for EGF, EGF receptor, IGF-1, LIF, and TNF-alpha. In conclusion, paragangliomas and pheochromocytomas are immunoreactive for a wide spectrum of growth factors and cytokines. Immunocytochemistry demonstrated similarities between sustentacular cells and stellate cells of the pituitary in addition to their similar morphology. The significance of these observations regarding paracrine activities of chief and sustentacular cells remains to be determined.
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PMID:Growth factors and cytokines in paragangliomas and pheochromocytomas, with special reference to sustentacular cells. 1244 18

To determine whether the pathophysiological processes after transient forebrain ischemia are mediated via a signal pathway involving gp130 (a signal transducer for the interleukin-6 family), we analyzed changes in the expression of gp130 and its downstream transcription factor, signal transducer and activator of transcription factor 3 (STAT3), in the rat hippocampus of a four-vessel occlusive ischemia model. Expression of gp130 mRNA was restricted to neurons of the pyramidal cell and granule cell layers in control animals. Four hours after ischemic injury, astrocytes expressed gp130 mRNA. Expression of gp130 increased preferentially in the CA1 and dentate hilar regions, and was maintained for at least 2 weeks. Increase in gp130 expression was accompanied by the activation of STAT3 following ischemic injury. Four hours after injury, STAT3 and phosphorylated STAT3 (pSTAT3) were observed in the nuclei of the dentate hilar region, and sequentially in the CA1 region at day 1. By day 3, STAT3 immunoreactivity markedly increased in these areas, where small cells with the morphology of astrocytes showed nuclear and cytoplasmic STAT3 and nuclear pSTAT3 immunoreactivities. These patterns were especially maintained in the CA1 area until 14 days of reperfusion. Double-labeling experiments revealed that the cells expressing STAT3 and pSTAT3 were glial fibrillary acidic protein-expressing reactive astrocytes. These results show a coordinated and long-lasting upregulation of gp130 mRNA and STAT3 activation in reactive astrocytes of the postischemic hippocampus, indicating that they may be involved in the astrocytic response to an ischemic insult.
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PMID:Upregulation of gp130 and STAT3 activation in the rat hippocampus following transient forebrain ischemia. 1252 79

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