Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binding characteristics and functional antagonism exerted by two structurally related tachykinin NK1 receptor antagonists, MEN 11467 ((1R,2S)-2N[1(H)indol-3-yl-carbonyl]-1-N-{Nalpha(p-tolylacetyl+ ++)-Nalpha(methyl)-D-3-(2-naphthyl)alanyl}diaminocyclohexane) and FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methy l-N-phenylmethyl-L-3-(2-naphthyl)alaninamide), were investigated in the human astrocytoma cell line U373 MG. In radioligand binding studies, conducted with [3H]substance P and intact cells at 37 degrees C, MEN 11467 bound to tachykinin NK1 receptors in an irreversible manner with a Ki value of 1.2+/-0.5 nM while FK888 bound in competitive manner with a Ki value of 4.6+/-2.2 nM. Receptor blockade by both antagonists resulted in a powerful and complete inhibition of functional responses induced by substance P, such as accumulation of the second messenger inositol monophosphate or interleukin-6 release. However, MEN 11467 showed a greater potency for blocking functional responses than FK888 despite their similar affinity for human tachykinin NK1 receptors. Moreover, MEN 11467 was more potent in inhibiting late rather than early phases of substance P-induced inositol monophosphate accumulation and its antagonism was enhanced by drug preincubation and barely affected by removal of unbound drug from the external medium, suggesting that MEN 11467 bound in a tight manner to the receptor. Such behaviour was not observed with the competitive and rapidly reversible antagonist FK888. These data indicate that the small differences in the chemical structure of MEN 11467 and FK888 determine the different binding characteristics at the tachykinin NK1 receptor and which are responsible for the greater potency of MEN 11467 for blocking functional responses. The Ki value obtained in binding studies may be inadequate to reveal the real potency of tachykinin NK1 receptor antagonists.
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PMID:Correlation between binding characteristics and functional antagonism in human glioma cells by tachykinin NK1 receptor antagonists. 1042 88

Tepoxalin is a structurally and functionally novel non-steroidal anti-inflammatory drug (NSAID) with potent anti-inflammatory and analgesic properties. Apart from its inhibitory effect on cyclooxygenase activity, tepoxalin is able to inhibit production of cytokines in peripheral cells outside the CNS. No data, however, are available concerning the effects of this drug in the CNS. Since cytokines such as interleukin-1 (IL-1) or interleukin-6 (IL-6) as well as acute-phase proteins such as alpha1-anti-chymotrypsin (ACT) participate in the etiopathology of Alzheimer's disease (AD), we were interested whether tepoxalin is able to inhibit the synthesis of these immunomodulators in primary rat microglia and astrocytes as well as in the human astrocytoma cell line U373 MG. We found that tepoxalin markedly inhibits IL-1beta-induced IL-6 and ACT synthesis in astrocytes and the synthesis of IL-1beta and IL-6 in lipopolysaccharide (LPS)-stimulated microglial cells. Electrophoretic mobility shift and reporter gene assays revealed that tepoxalin exerts its inhibitory effect through the inhibition of nuclear factor kappaB (NF-kappaB), a transcription factor involved in the induction of IL-1, IL-6 and ACT gene expression. We show that inhibition of NF-kappaB activation by tepoxalin is mediated by preventing IkappaB-alpha degradation. Based on this inhibitory effect of tepoxalin on cytokine and ACT synthesis and the documented therapeutic efficacy of NSAIDs in AD, we conclude that tepoxalin may be of therapeutic benefit for the treatment of AD patients and should therefore be tested in clinical trials.
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PMID:The non-steroidal anti-inflammatory drug tepoxalin inhibits interleukin-6 and alpha1-anti-chymotrypsin synthesis in astrocytes by preventing degradation of IkappaB-alpha. 1047 Oct 86

We evaluated the effects of 50 Hz pulsed electromagnetic fields (EMFs) with a peak magnetic field of 3 mT on human astrocytoma cells. Our results clearly demonstrate that, after the cells were exposed to EMFs for 24 h, the basal [Ca(2+)](i) levels increased significantly from 124+/-51 nM to 200+/-79 nM. Pretreatment of the cells with 1.2 microM substance P increased the [Ca(2+)](i) to 555+/-278 nM, while EMF exposure caused a significant drop in [Ca(2+)](i) to 327+/-146 nM. The overall effect of EMFs probably depends on the prevailing Ca(2+) conditions of the cells. After exposure, the proliferative responses of both normal and substance P-pretreated cells increased slightly from 1.03 to 1.07 and 1.04 to 1.06, respectively. U-373 MG cells spontaneously released about 10 pg/ml of interleukin-6 which was significantly increased after the addition of substance P. Moreover, immediately after EMF exposure and 24 h thereafter, the interleukin-6 levels were more elevated (about 40%) than in controls. On the whole, our data suggest that, by changing the properties of cell membranes, EMFs can influence Ca(2+) transport processes and hence Ca(2+) homeostasis. The increased levels of interleukin-6 after 24 h of EMF exposure may confirm the complex connection between Ca(2+) levels, substance P and the cytokine network.
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PMID:The effect of pulsed electromagnetic fields on the physiologic behaviour of a human astrocytoma cell line. 1111 42

Glial cells release neurotrophic factors that maintain neurons functionally. Previously, we have shown that the scabronines isolated from Sarcodon scabrosus enhanced the secretion of neurotrophic factors from 1321N1 human astrocytoma cells. In the present study, we examined the mechanism of newly synthesized scabronine G-methylester (ME)-induced secretion of neurotrophic factors from 1321N1 cells. The dramatic neuronal differentiation of rat pheochromocytoma cells (PC-12) was observed by scabronine G-ME-conditioned medium of 1321N1 cells. Scabronine G-ME increased the secretion of nerve growth factor (NGF) and interleukin-6 (IL-6) from 1321N1 cells with the enhancement of their mRNA expressions. Scabronine G-ME concentration-dependently inhibited the carbachol-induced inositol phosphate accumulation in 1321N1 cells, which was reversed by GF109203X, an inhibitor of protein kinase C (PKC) isoforms. Furthermore, GF109203X inhibited the scabronine G-ME-induced mRNA expressions of both NGF and IL-6 and the differentiation of PC-12 cells, showing that scabronine G-ME activated PKC. Although scabronine G-ME enhanced activities of neither conventional nor novel types of PKCs, it translocated PKC-zeta to membranes in intact cells and cell-free condition. Furthermore, recombinant PKC-zeta activity was also increased by scabronine G-ME, suggesting the involvement of PKC-zeta in the effect of scabronine G-ME. Concerning the downstream effectors of the PKC-zeta, scabronine G-ME translocated nuclear factor-kappaB to nucleus, and enhanced its transcriptional activity. In addition, scabronine G-ME caused the degradation of inhibitor of nuclear factor-kappaB concentration-dependently, which was inhibited by GF109203X. These results suggest that scabronine G-ME potentially enhances the secretion of neurotrophic factors from 1321N1 cells mediated via the activation of PKC-zeta.
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PMID:Scabronine G-methylester enhances secretion of neurotrophic factors mediated by an activation of protein kinase C-zeta. 1130 14

We tested the hypothesis that extracts from St. John's wort interfere with protein synthesis induced by substance P (SP), a neuropeptide which has been implicated in the etiopathology of depression and anxiety. Using human astrocytoma cells, which express functional neurokinin (NK)-1-receptors, we investigated whether extracts from St. John's wort are able to inhibit SP-induced synthesis of the cytokine interleukin-6 (IL-6). We found a potent and dose-dependent inhibition of SP-induced IL-6 synthesis by various extracts from St. John's wort. These results do not only give further evidence of the anti-inflammatory effects of St. John's wort, but also lend support to the hypothesis that the antidepressant effect of St. John's wort is, at least in part, a result of its inhibitory effects on SP-induced protein synthesis.
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PMID:Inhibition of substance P-induced cytokine synthesis by St. John's wort extracts. 1151 71

The expression of cyclooxygenase-2 (COX-2) and the synthesis of prostaglandin E2 (PGE2) as well as of cytokines such as interleukin-6 (IL-6) have all been suggested to propagate neuropathology in different brain disorders such as HIV-dementia, prion diseases, stroke and Alzheimer's disease. In this report, we show that PGE2-stimulated IL-6 release in U373 MG human astroglioma cells and primary rat astrocytes. PGE2-induced intracellular cAMP formation was mediated via prostaglandin E receptor 2 (EP2), but inhibition of cAMP formation and protein kinase A or blockade of EP1/EP2 receptors did not affect PGE2-induced IL-6 synthesis. This indicates that the cAMP pathway is not part of PGE2-induced signal transduction cascade leading to IL-6 release. The EP3/EP1-receptor agonist sulprostone failed to induce IL-6 release, suggesting an involvement of EP4-like receptors. PGE2-activated p38 mitogen-activated kinase (p38 MAPK) and protein kinase C (PKC). PGE2-induced IL-6 synthesis was inhibited by specific inhibitors of p38 MAPK (SB202190) and PKC (GF203190X). Although, up to now, EP receptors have only rarely been linked to p38 MAPK or PKC activation, these results suggest that PGE2 induces IL-6 via an EP4-like receptor by the activation of PKC and p38 MAPK via an EP4-like receptor independently of cAMP.
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PMID:Mechanisms of prostaglandin E2-induced interleukin-6 release in astrocytes: possible involvement of EP4-like receptors, p38 mitogen-activated protein kinase and protein kinase C. 1173 6

A chronic inflammatory response associated with beta-amyloid (Abeta) and interleukin-1beta (IL-1beta) is responsible for the pathology of Alzheimer's disease (AD). Astrocytes are predominant neuroglial cells of the central nervous system and are actively involved in cytokine-mediated events in AD. To investigate the biological effect of water-soluble chitosan (WSC), we examined cytotoxicity, production of pro-inflammatory cytokines and inducible nitric-oxide synthase (iNOS) on human astrocytoma cell line CCF-STTG1 stimulated with IL-1beta and Abeta fragment 25-35 (Abeta[25-35]). In 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide colorimetric assay, WSC by itself had no effect on cell viability on human astrocytoma cells. The effects of WSC on tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were evaluated with enzyme-linked immunosorbent assay and Western blotting. The production of TNF-alpha and IL-6 was induced by IL-1beta and Abeta[25-35] and synergistically amplified by the co-stimulation of IL-1beta and Abeta[25-35]. The secretion and expression of pro-inflammatory cytokines, TNF-alpha and IL-6, was significantly inhibited by pretreatment with WSC in human astrocytoma cells. The expression of iNOS was induced by IL-1beta and Abeta[25-35] and was partially inhibited by treatment with WSC. We demonstrate the regulatory effects of WSC in human astrocytes for the first time and suggest the anti-inflammatory effect of WSC may reduce and delay AD pathologic events.
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PMID:Water-soluble chitosan inhibits the production of pro-inflammatory cytokine in human astrocytoma cells activated by amyloid beta peptide and interleukin-1beta. 1187 67

Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E(2) (PGE(2)), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE(2) production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE(2) production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE(2) production by OSM and IL-1beta treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE(2) synthesis. Of the enzymes involved in PGE(2) biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1beta. Nuclear run-on assays demonstrate that OSM and IL-1beta synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1beta. To effect synergy on the PGE(2) level, OSM signals in part through its gp130/OSMRbeta receptor, since neutralizing antibodies against gp130 and OSMRbeta, but not LIFRbeta, decrease PGE(2) production in response to OSM plus IL-1beta. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1beta and OSM upregulation of COX-2 and PGE(2), indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE(2) amplification may be active in brain pathologies where both OSM and IL-1beta are present, such as glioblastomas and multiple sclerosis.
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PMID:Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: synergy with interleukin-1beta, tumor necrosis factor-alpha, and bacterial lipopolysaccharide. 1273 Sep 64

The neuropeptide substance P (SP) has been hypothesized to be involved in the etiopathology of affective disorders. This hypothesis is based on the findings that neurokinin-1-receptor antagonists have antidepressant effects in depressed patients and that SP may worsen mood. In this study, we investigated the effect of the mood-stabilizing agents valproic acid (VPA), carbamazepine, and lithium on SP-induced gene expression. As a model system, we used primary rat astrocytes and human astrocytoma cells, which both express functional SP-receptors and, upon stimulation with SP, synthesize interleukin-6 (IL-6), a cytokine which has been shown to be elevated during the acute depressive state. We found that VPA dose-dependently inhibited SP-induced IL-6 synthesis which was seen with pre-incubation periods of 30 min, 3, 7 and 14 days, whereas carbamazepine and lithium showed no inhibitory effect. The inhibitory effect of VPA was not mediated by inhibition of the stress-regulated kinases p38 and p42/44 (Erk1/2) but by inhibition of protein kinase C epsilon activation. Furthermore, VPA down-regulated the expression of the substance P receptor (neurokinin(NK)-1-receptor) as assessed by real-time PCR. Whether both mechanisms contribute to the mood-stabilizing properties of VPA has to be evaluated in further studies.
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PMID:Valproic acid inhibits substance P-induced activation of protein kinase C epsilon and expression of the substance P receptor. 1280 26

The pleiotropic cytokine interleukin-6 (IL-6) contributes to malignant progression and apoptosis resistance of various cancer types. Although IL-6 is elevated in malignant gliomas, and glioma cells respond to IL-6, its functional role in gliomagenesis is unclear. We have investigated this role of IL-6 in a mouse model of spontaneous astrocytoma by crossbreeding glial fibrillary acidic protein (GFAP)-viral src oncogene transgenic mice with IL-6-deficient mice. We show here that ablation of IL-6 prevents tumour formation in these predisposed animals, but did not affect preneoplastic astrogliosis. Moreover, we demonstrate phosphorylation and nuclear translocation of the transcription factor signal transducer and activator of transcription (STAT)3, a prerequisite for IL-6 signalling, in 51 human gliomas WHO grade II-IV and all experimental mouse tumours investigated. Together with the observation that STAT3 activation increases with malignancy, these findings indicate an important role for IL-6 in the development and malignant progression of astrocytomas.
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PMID:IL-6 is required for glioma development in a mouse model. 1506 29


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