UNIPROT:P05231 - FACTA Search

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)

beta-Amyloid protein (betaA) has been implicated in the pathogenesis of Alzheimer's disease (AD) because of its neurotoxicity and ability to trigger a local inflammatory response. Although assembly of betaA in particular aggregates seems to be crucial event in AD pathogenesis, soluble, non-fibrillar betaA may also be involved. Non-fibrillar betaA1-42, and truncated peptide 1-28, induced dose-dependent activation of C4 sparing C3. The mechanism of C4 activation was not dependent on C1q, because non-fibrillar betaA can still activate C4 in plasma genetically deficient in C1q. A C1q independent mechanism of complement classical pathway activation could be via the activation of contact/kinin system. The possible involvement of contact system in AD is suggested by the finding that this system is massively activated in CSF of AD patients. The mechanism of activation of contact system could be the result of an anionic interaction of residues within the region 1-11 of betaA1-42 with factor XII, and of kallikrein generation. Concomitant incubation of a small cationic peptide (lysine4) with betaA abrogated its ability to trigger the cleavage of high molecular weight kininogen. In vivo, prevention of contact system activation beside the reduction of kallikrein generation, can also decrease the activation of complement system and the release of interleukin-6, both factors being considered to play an important role in the inflammatory reactions in AD brain.
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PMID:Activation of complement and contact system in Alzheimer's disease. 1158 15

To determine the possible contribution of glial cells via oxidative stress/cytokine secretion in the pathogenesis of Parkinson's disease (PD), Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) the concentration of nitric oxide (NO) (by the Griess method) and Interleukin-6 (IL-6) (by enzyme-linked immunosorbent assay) were measured in resting rat microglial and astrocytic cell culture supernatants stimulated by cerebrospinal fluid (CSF) (dilution 1:4, 1:10) from patients with the aforementioned diseases. Neither the concentration of NO (optical density at 450 nm: control, 0.036+/-0.006; MS, 0.034+/-0.008; AD, 0.031+/-0.006; PD, 0.02+/-0.01; lipopolysaccharide (LPS), 0.26+/-0.018) nor the amount of IL-6 (ng/ml: control, 0.112+/-0.026; PD, 0.12+/-0.027; MS, 0.123+/-0.008; ALS, 0.137+/-0.01; LPS, 1.81+/-0.11) differed in any disease group from those of unaffected controls. These findings suggest that the stimuli for inflammatory activation of glia are quite localized and not present in sufficient concentrations in the CSF of affected patients.
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PMID:Cerebrospinal fluid from patients with neurodegenerative and neuroinflammatory diseases: no evidence for rat glial activation in vitro. 1170 95

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

Neuroinflammation is a central feature of Alzheimer disease (AD). It involves an innate immune reaction of sufficient intensity that self attack on neurons occurs. This phenomenon is best described as autotoxicity to distinguish it from classical autoimmunity which involves cloning of peripheral lymphocytes. Many compounds have been identified in AD brain which are known to promote and sustain inflammatory responses. They include beta-amyloid protein; the pentraxins C-reactive protein and amyloid P; complement proteins; the inflammatory cytokines interleukin-1, interleukin-6 and tumor necrosis factor-alpha; the protease inhibitors alpha-2-macroglobulin and alpha-1-antichymotrypsin; and the prostaglandin generating cyclooxygenases COX-1 and COX-2. Orally effective agents which can counteract the influence of these inflammatory stimulators should be effective in treating AD. Epidemiological evidence, coupled with results from pilot clinical trials, suggest there is great promise for traditional COX-1 inhibiting NSAIDs. Inhibitors of mediators closer to the core processes might offer even greater therapeutic promise. Some theoretical opportunities are suggested, based on intervention in the action of the above mentioned mediators.
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PMID:Inflammation, autotoxicity and Alzheimer disease. 1175 86

Various hormones can influence the expression of interleukin-6 (IL-6) and oestrogens are the most extensively studied. There is, however, controversy about the nature of the IL-6 secreted by human cells and its regulation by 17beta-oestradiol. The aim of this work was to clarify whether oestrogen deprivation after menopause may contribute to an enhanced IL-6 production by peripheral blood mononuclear cells (PBMC) in postmenopausal women. Twenty-two healthy postmenopausal women, age range 45-63 years, with clinical symptoms of oestrogen deficiency were enrolled in the study. The control group consisted of 16 healthy young women, age range 22-31 years, with regular menses and who were not taking oral contraceptives. Levels of IL-6 in the sera and PBMC culture supernatants were measured by the biological B9 cell-proliferation assay and expression of the IL-6 gene in non-stimulated PBMC was detected by RT-PCR. The effect of 17beta-oestradiol on spontaneous IL-6 production by the PBMC of postmenopausal women was also studied in vitro and in vivo. Seventeen out of the twenty-two postmenopausal women were given hormonal replacement therapy of 50 microg 17beta-oestradiol/day transdermally and the spontaneous production of IL-6 by the PBMC was analysed after 6 and 12 months of treatment. The postmenopausal women had significantly higher serum levels of IL-6 than the young controls. The spontaneous production of IL-6 by non-stimulated PBMC into the culture supernatants was also significantly higher in the postmenopausal women compared with the young. We also found that IL-6 gene expression was present in the non-stimulated PBMC isolated directly from the venous blood of the majority of the postmenopausal women. Women with IL-6 gene expression in the non-stimulated PBMC had significantly lower serum levels of 17beta-oestradiol compared with those where the IL-6 gene was not expressed in the PBMC. Our in vitro experiments showed that 17beta-oestradiol at concentrations of 10(-9) M and 10(-10) M decreased spontaneous IL-6 production by the PBMC of postmenopausal women. In vivo treatment with 17beta-oestradiol transdermally also significantly decreased spontaneous IL-6 production by the PBMC of postmenopausal women after 12 months of the therapy. Our results indicate that oestrogen deprivation after menopause may enhance IL-6 production by the PBMC of postmenopausal women. We suspect that the late complications of oestrogen deficiency, such as osteoporosis, coronary heart disease and Alzheimer's disease, may be mediated by an exaggerated production of IL-6 - a cytokine which seems to play a pivotal role in the pathogenesis of these age-related diseases.
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PMID:Effects of oestrogen deprivation on interleukin-6 production by peripheral blood mononuclear cells of postmenopausal women. 1183 56

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are weak androgens produced primarily by the adrenal gland. Although their plasma concentrations by far exceed those of any other adrenal product, their physiological roles have not yet been determined. In plasma, where the major portion of these hormones is present in the sulfate form, it is possible that DHEAS serves as a reservoir for DHEA. Since various tissues have been shown to contain steroid sulfatases. The peak plasma levels of DHEA and DHEAS occur at approximately age 25 years, decrease progressively thereafter, and diminish by 95 per cent around the age of 85 years. The decline of DHEAS concentrations with aging has led to the suggestion that DHEAS could play a role in itself and be implicated in longevity. Moreover, the epidemiological evidence has shown that adult men with high plasma DHEAS levels are less likely to die of cardiovascular disease. DHEA has also been shown to increase the body's ability to transform food into energy and burn off excess fat. Another recent finding involves the anti-inflammatory properties of DHEA. It has been known that DHEA can lower the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). It should be pointed out that chronic inflammation is known to play a critical role in the development of the killer diseases of aging: heart disease, Alzheimer's disease and certain types of cancer. In conclusion, DHEA or DHEAS administration combined with conventional treatment may be implicated in particular conditions to improve the quality of life.
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PMID:DHEA(S): the fountain of youth. 1185 89

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

Inflammatory events have been associated with senile plaques, one of the pathological hallmarks of Alzheimer's disease (AD). It is believed that aggregated beta-amyloid (betaA) proteins, which form the core of these plaques, may be responsible for triggering the inflammatory reaction. In the present study, the ability of aluminum (Al) to initiate similar inflammatory events was investigated in a human glioblastoma cell line. A 6-day exposure to either lipopolysaccharide (LPS) or aluminum sulfate caused a significant increase in the rate of proliferation of the glioblastoma cells. Both treatments also caused activation of the immune-responsive transcription factor NF-kappaB although there were time-related differences. The levels of secreted cytokines, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were both increased by the LPS treatment although exposure to Al decreased the secretion of the former while elevating the levels of the latter. These events may be due to the activation of glial cells and subsequent stress response to either Al complexes or LPS. Although exposure to either stress factor caused a stimulation of inflammatory markers, there were time-dependent differences in the response. This may reflect the ability of the cells to discern different stress factors and thus orchestrate an innate immune response profile distinct to each immunogen.
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PMID:Pro-inflammatory effects of aluminum in human glioblastoma cells. 1192 36

Interleukin-6 (IL-6), an inflammatory cytokine might be involved in the pathophysiology of Alzheimer disease (AD); several studies have reported that the "C allele of IL-6 variable number of tandem repeat polymorphism" (IL-6vntr) delayed initial onset of AD and also decreased its risk per se. Another polymorphism, G/C allele of IL-6 gene promoter region (IL-6prom), is also a candidate because it has an influence on the regulation of plasma IL-6 concentration. We examined these IL-6 polymorphisms in 128 Japanese AD cases and 83 control cases using a PCR-RFLP method. The results showed the frequency of the IL-6prom G allele was significantly increased in AD, although IL-6vntr polymorphism was not. Plasma IL-6 concentration of the AD cases was also significantly higher than that of the control cases. Moreover, the IL-6prom G allele-positive AD patients showed a tendency to have higher IL-6 concentration in the AD group. These findings suggest that the IL-6prom G allele which may affect plasma IL-6 concentration might be a risk factor for sporadic AD in Japanese.
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PMID:Effect of IL-6 polymorphism on risk of Alzheimer disease: genotype-phenotype association study in Japanese cases. 1199 67

Interleukin-6 (IL-6) is a multifunctional cytokine playing a crucial role in inflammation and tissue injury. A role for this molecule in neurodegeneration and Alzheimer's disease (AD) has been proposed. The aim of this study was to evaluate the association between a common polymorphism of the IL-6 gene promoter and AD in the Italian population. We found that the frequency of the GG genotype was significantly higher in AD patients than controls on both univariate ( rho< 0.0001) and multivariate analysis ( rho< 0.0001). In contrast, the CC genotype seems to be associated with a reduced risk of disease ( rho< 0.0001). Our data indicate that the IL-6 gene polymorphism is associated with AD in Italians and confirm that IL-6 is crucial in the pathophysiology of neurodegenerative disorders.
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PMID:The -174 G/C polymorphism of the interleukin-6 gene promoter is associated with Alzheimer's disease in an Italian population [corrected]. 1235 19

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