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

The direct in vitro effect of interleukin-6 (IL-6) on pancreatic beta-cells was studied using isolated Lewis rat islets (25/ml/well) precultured for 7 days and then incubated with or without human recombinant IL-6 (rIL-6) or purified human natural IL-6 (nIL-6). Both sources of IL-6 stimulated insulin secretion over a period of 6 days (P less than 0.01), whereas the levels of insulin within the islets were unaffected. At concentrations above 1.5 ng/ml, rIL-6 almost doubled the content of insulin in the supernatants. At an intermediate concentration, 0.5 ng/ml, rIL-6 preserved insulin secretion by islets cocultured with 2 ng/ml of human recombinant interleukin 1 beta (rIL-1 beta) which otherwise inhibited insulin secretion to 60% of islets cultured in medium alone. Electron microscopic studies showed that rIL-6, 1.5 ng/ml, caused beta-cell specific degenerative changes similar to those previously described after treatment with IL-1 beta; i.e. appearance of opaque intracytoplasmic bodies, autophage vacuoles and signs of mitochondrial degeneration. We conclude that human IL-6 stimulates insulin production and secretion in vitro and induces similar ultrastructural changes in beta-cells as does IL-1 beta. IL-6 may be an endogenous mediator of some of the effects on beta-cells ascribed to IL-1.
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PMID:Interleukin 6: a functional and structural in vitro modulator of beta-cells from islets of Langerhans. 212 51

Evidence from epidemiological and histopathologic studies in humans with autoimmune type 1 (insulin-dependent) diabetes suggests that beta-cell destruction within the islets of Langerhans progresses through a number of stages. In this review we draw on recent experimental evidence in an attempt to define the molecular pathology of these stages. Stage 1 is postulated to be initiated by modification of the beta cell by virus, chemical or other factors, leading to the production of interferon-alpha, hyperexpression of major histocompatibility complex (MHC) class I molecules and induction of MHC class II molecules. Experiments in transgenic mice suggest that overexpression of MHC molecules is in itself detrimental to beta-cell function. Shedding of antigen(s) from dying beta cells in combination with hyperexpression of MHC molecules may be a powerful immunogenic stimulus. Stage 2 commences with infiltration of the islets by immuno-inflammatory cells (termed insulitis). It is proposed that production of cytokines from the infiltrating cells induces "phenotypic switching" in beta cells, with further upregulation of MHC molecules and the induction of intracellular adhesion molecule-1 expression and interleukin-6 production. Together, these properties are seen as a prerequisite for the presentation of autoantigen by beta cells to adherent T lymphocytes and autoimmune activation. The final stage encompasses autoimmune-mediated destruction of the beta cells by the targeted delivery of cytotoxic cytokines and other mediators.
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PMID:Molecular pathology of type 1 diabetes. 223 44

Glucose-induced insulin secretion from islets cultured in the presence of interleukin-6 (IL-6) for 12-24 h was inhibited to a similar extent as when islets were treated with interleukin-1 beta (IL-1 beta). However, unlike IL-1 beta, IL-6 did not potentiate insulin secretion during an acute (30 min) exposure of islets to the cytokine, nor did it inhibit DNA synthesis during a 24 h culture period. A 12 h pretreatment of islets with tumour necrosis factor-alpha (TNF-alpha) combined with IL-1 beta potentiated the inhibitory effect of IL-1 beta on secretion, such that 20 mM-glucose-induced insulin secretion was abolished. No synergistic inhibition of secretion was observed with TNF-alpha and IL-6. However, IL-1 beta and IL-6 were found to inhibit insulin secretion in an additive manner. These results suggest that IL-6 inhibits insulin secretion in a manner distinct from that of IL-1 beta, and that IL-6 is unlikely to mediate the inhibitory effects of IL-1 beta or TNF-alpha on rat islets of Langerhans.
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PMID:Inhibition of insulin secretion from rat islets of Langerhans by interleukin-6. An effect distinct from that of interleukin-1. 226 29

Recently it has been postulated that interleukin-1 (IL-1) locally released by infiltrating mononuclear cells may destroy the pancreatic B cells during the development of insulin-dependent diabetes mellitus. Since IL-1 is a potent inducer of interleukin-6 (IL-6) in various cells, it is conceivable that IL-6 is a second mediator of the IL-1 action. In the present study the effects of IL-6 alone or in combination with IL-1 were studied on pancreatic islet function in vitro after tissue culture and compared with the effects observed after exposure to IL-1 only. Rat pancreatic islets were cultured in medium RPMI 1640 + 10% calf serum with or without the addition of human recombinant IL-6 (500-5000 pg/ml) for 48 h. The medium insulin accumulation was increased by 40-50% after culture with 500-2000 pg/ml IL-6, but was similar to the controls at 5000 pg/ml. When islets were cultured for 18 h only, also 5000 pg/ml IL-6 stimulated the medium insulin accumulation. IL-6 did not affect the islet insulin content and the rates of islet (pro)insulin and total protein biosynthesis. It inconsistently decreased the islet DNA content. In short-term experiments after 48-h culture with IL-6, there was a dose-dependent inhibition of the glucose-stimulated insulin release. On the other hand, islets cultured with IL-6 (5000 pg/ml) exhibited an elevated glucose oxidation and oxygen uptake, but a lower ATP content at 16.7 mM glucose and an unaffected glucose utilization and glutamine oxidation compared to the controls. This raises the possibility that IL-6 had induced a condition with an increased energy expenditure, resulting in an enhanced mitochondrial metabolism of glucose. Islets cultured with human recombinant IL-1 beta (25 units/ml) showed a strong inhibition of the insulin accumulation in the culture medium and of glucose-stimulated insulin release and a marked decrease in the islet DNA and insulin content. A combination of IL-1 (25 U/ml) + IL-6 (1000 pg/ml) did not alter the inhibitory action of IL-1 alone. The present findings thus show that IL-6 induces a dissociation between insulin secretion and glucose oxidation in islets in vitro. This has not been observed in islets exposed to IL-1, which suggests that IL-6 does not solely mediate the inhibitory effects of IL-1 on islet function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-6 affects insulin secretion and glucose metabolism of rat pancreatic islets in vitro. 240 46

Immune responses result in a variety of metabolic adjustments that are mediated by cytokines of leukocytic origin. Of the dozens of cytokines released during an immune response, interleukin-1 (IL-1), tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) are the major mediators of intermediary metabolism. These three cytokines act in concert to decrease food intake, increase resting energy expenditure, gluconeogenesis, glucose oxidation, and hepatic synthesis of fatty acids and acute phase proteins, decrease fatty acid uptake by adipocytes and alter the distribution of zinc, iron and copper. Most of these activities result from direct interactions between the cytokine and the responding cells. IL-1, TNF alpha and IL-6 also affect changes in metabolism by changing levels of circulating insulin, glucagon and corticosterone. The nutritional impact of these metabolic changes is dependent upon age. In growing animals, increases in energy expenditure and oxidation of amino acids are balanced by lower needs associated with growth. In adult animals, energy and amino acid requirements are increased by an amount similar to the increased basal metabolic rate and amino acid oxidation. Nutrition also influences the release of cytokines and consequently affects regulation of the immune response. For example, protein deficiency results in decreased IL-1 release and impaired tissue responses to IL-1.
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PMID:Nutritional aspects of leukocytic cytokines. 306 44

Insulin-like growth factor binding proteins (IGF BP) and insulin-like growth factors (IGF) secretion by differentiating chondrocytes, derived from mouse embryonic limb bud and responsive to both IGF-I and -II [23], was investigated. The Western ligand blot analysis of the conditioned medium (CM) from days 1, 3, 5 and 7 of culture revealed the secretion of IGF BP of approx. 35-40, 28-30 and 24-26 kDa. The 35-40 kDa protein which comigrated with the 40 kDa protein in CM of trophoblast cells identified as IGF BP-3. The 28-30 kDa protein was identified as IGF BP-2 by Western immunoblotting with alpha-IGF BP-2 antisera. The 24-26 kDa protein was consistent with the nonglycosylated form of IGF BP-4. Secretion of three IGF BPs were increased with the age of the culture. This suggested that the major IGF BP secreted by differentiating chondrocytes in culture are IGF BP-2, -3 and -4. All three of these IGF BPs were stimulated by both IGF-I and -II. IGF-I was approx. 2-fold more potent than IGF-II. The investigation of the localized production of IGF revealed that chondrocytes, similar to IGF BP, secreted IGF-II in differentiation dependent manner. No IGF-I secretion was identified. Examination of the secretion of solubilized IGF-II receptor by the chondrocytes, in contrast to trophoblasts, failed to reveal the presence of IGF-II receptor in the CM. This suggested that, unlike many other cells, including trophoblasts, chondrocytes do not secrete solubilized IGF-II receptor. In summary, the present results suggested an interactive autocrine/paracrine action of IGF BP and IGF-II in the chondrocytes, while the IGF-I action is predominantly endocrine.
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PMID:Insulin-like growth factor (IGF) binding proteins and insulin-like growth factor secretion by cultured chondrocyte cells: identification, characterization and ontogeny during cell differentiation. 750 58

We have studied transcription factors that are coupled to the activation of cytokine receptors in liver and in mammary epithelial cells. Interleukin-6 (IL-6) causes the rapid activation of the acute-phase response factor (APRF) in the liver of animals during acute inflammation and in cultured human hepatoma cells (HepG2) and induces the transcription of the acute-phase protein genes, e.g. alpha 2-macroglobulin (alpha 2-M). In the mammary gland and in cultured HC11 mammary epithelial cells, milk protein genes, e.g. beta-casein, are induced by the lactogenic hormones, insulin, glucocorticoids, and PRL. The induction of the beta-casein gene promoter is preceded by the activation of the mammary gland factor (MGF). We have compared the DNA binding sequences of APRF and MGF, 5'-CTTCTT/GGGAATT-3', and have found that they coincide in 11 of 12 positions. Bandshift experiments and oligonucleotide competition experiments showed that both factors, MGF and APRF, are able to bind to the IL-6 response element of the alpha 2-M gene promoter and to the lactogenic hormone response element of the beta-casein gene promoter with very similar specificities. Partial proteolytic digestion of APRF and MGF DNA complexes yielded similar clipping patterns. The UV cross-linked DNA complexes of both transcription factors were of the same apparent molecular mass. IL-6 activation of APRF in HepG2 cells can be observed within minutes. MGF induction by PRL in HC11 cells occurs with similar kinetics. The synergistic action of glucocorticoids and PRL is necessary for the induction of the beta-casein gene, but PRL is sufficient for MGF activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mammary gland factor activated by prolactin on mammary epithelial cells and acute-phase response factor activated by interleukin-6 in liver cells share DNA binding and transactivation potential. 751 23

The insulin secreting rat Rinm5F cells are often used to study the cytotoxic actions of interleukin-1 (IL-1) on pancreatic beta-cells. We demonstrate here that Rinm5F insulinoma cells express both type I and type II interleukin-1 receptor (IL-1R) mRNAs and gene products. IL-1R agonists, recombinant murine IL-1 alpha (rmIL-1 alpha, 10 ng/ml) and recombinant rat IL-1 beta (rrIL-1 beta, 100 pg/ml or 10 ng/ml) induce the upregulation of mRNA expression for both types of IL-1 receptors (IL-1Rs). This effect of rrIL-1 beta is antagonised by preincubation with recombinant human interleukin 1 receptor antagonist protein (rhIL-1ra, 5 micrograms/ml). Furthermore, this rrIL-1 beta induced upregulation of IL-1R mRNAs is blocked by actinomycin D (7.5 micrograms/ml), whereas cycloheximide (20 micrograms/ml) has no effect. The phorbol ester PMA (20 nM) upregulates the expression of mRNAs both IL-1 receptors, whereas glucose (50 mM) upregulates the expression of the type I IL-1R mRNA only. Pretreatment of cells with pertussis toxin (100 ng/ml) partially blocks the rrIL-1 beta induced expression of mRNA for the type I and, to a lesser extent, the type II IL-1R. Incubation of the cells with rrIL-1 beta also induces a time-dependent expression of c-fos, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) mRNAs. Binding studies with 125I-recombinant human IL-1 beta (125I-rhIL-1 beta) indicate that IL-1R gene products, with the ligand binding characteristics of the type I IL-1R, are constitutively present on Rinm5F cells. Treatment with rrIL-1 beta (6h) increases the number of 125I-rhIL-1 beta binding sites on Rinm5F cells. We have also demonstrated that the number of type II IL-1R binding sites increases after induction with rrIL-1 beta (6h), by indirect immunofluorescence using a monoclonal antibody (ALVA 42) raised against the human type II IL-1R. Furthermore, we have sequenced the type II IL-1R cDNA in the rat insulinoma Rinm5F cells. The comparison of the amino acid sequence of the rat type II IL-1R with that of the mouse and human type II IL-1Rs shows 90% and 62% amino acid identity, respectively. The most important difference between the human and murine type II IL-1Rs, and this rat type II IL-1R cDNA, is an open reading frame coding for a six amino acid longer, strongly charged (QIKEMK), cytosolic domain.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interleukin-1 stimulates the expression of type I and type II interleukin-1 receptors in the rat insulinoma cell line Rinm5F; sequencing a rat type II interleukin-1 receptor cDNA. 752 17

The influence of recombinant human interleukin-6, the major mediator of the inflammatory response in liver, on the glucagon- and insulin-dependent induction of the phosphoenolpyruvate carboxykinase and glucokinase gene, respectively, was monitored on the level of gene transcription, mRNA abundance and enzyme activity in cultured rat hepatocytes. As control markers of the interleukin-6-induced acute-phase response the mRNA levels of the acute phase proteins alpha 2-macroglobulin and beta-fibrinogen were determined. In cultured rat hepatocytes, recombinant human interleukin-6, added simultaneously with glucagon and insulin, lowered the maximal increase in glucagon-induced phosphoenolpyruvate carboxykinase mRNA levels after 2 hr and the maximal increase in glucokinase mRNA levels after 3 hr to about 30%, respectively. It inhibited the glucagon-induced increase in phosphoenolpyruvate carboxykinase gene transcription and phosphoenolpyruvate carboxykinase enzyme activity, as well as the insulin-induced increases in glucokinase gene transcription and glucokinase enzyme activity. Recombinant human interleukin-6 increased the mRNA levels of the acute-phase proteins alpha 2-macroglobulin and beta-fibrinogen gradually over 4 to 6 hr. Recombinant human interleukin-6, added 2 hr after glucagon or 3 hr after insulin at the maximum of the hormone-induced enzyme mRNA levels, almost doubled the decay rate of phosphoenolpyruvate carboxykinase mRNA and glucokinase mRNA. The results show that interleukin-6 induced the expression of inflammatory proteins and simultaneously inhibited the hormone-induced expression of enzymes of intermediary metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition by recombinant human interleukin-6 of the glucagon-dependent induction of phosphoenolpyruvate carboxykinase and of the insulin-dependent induction of glucokinase gene expression in cultured rat hepatocytes: regulation of gene transcription and messenger RNA degradation. 752 6

The regulation of acute phase protein production and the relationship of the acute phase protein response to tumour growth was examined in colorectal cancer patients (n = 9). Ibuprofen (1200 mg/d) was administered for 8-11 days. Following ibuprofen administration there were reductions in circulating concentrations of C-reactive protein (P = 0.01), interleukin-6 (P = 0.06), cortisol (P = 0.04) and also in the platelet count (P = 0.01). There was no significant change in albumin, insulin and carcinoembryonic antigen. These results indicate that ibuprofen administered over a prolonged period substantially reduces acute protein production via its effect on interleukin-6 and cortisol. It remains to be determined whether ibuprofen is useful in moderating tumour growth in colorectal cancer patients.
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PMID:Effect of extended ibuprofen administration on the acute phase protein response in colorectal cancer patients. 758


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