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)

During vascular injury, such as observed in atherosclerosis, restenosis, vasculitides, transplantation, or sepsis, vascular smooth muscle cells (SMC) can be exposed to platelets or platelet products. Under these conditions proliferation or cytokine production of SMC stimulated by platelets or platelet products may contribute to regulation of vascular pathogenesis. Thus, we investigated interleukin-6 (IL-6) and IL-8 production as well as proliferation of SMC in response to platelets or platelet lysates. Platelets not already preactivated by thrombin induced IL-6 (10- to 50-fold) or IL-8 production of unstimulated SMC in a cell number dependent fashion. Preactivation of platelets with thrombin potently increased the platelet-mediated IL-6 (50- to 1,000-fold) and IL-8 production of SMC. Hirudin specifically inhibited the activation of platelets with thrombin. Isolated platelets cultured in the absence of SMC did not contain detectable IL-6 or IL-8. Prestimulation (4 hours) of SMC with pathophysiologically relevant substances (lipopolysaccharide [LPS], tumor necrosis factor-alpha [TNF-alpha], or IL-1alpha) further increased the platelet-induced cytokine production. The platelet-derived SMC stimulatory activity was IL-1, since IL-1 receptor antagonist (IL-1-Ra) inhibited the platelet-induced cytokine production of SMC. Anti-platelet-derived growth factor (PDGF)-antibody did not further reduce this activity. Thrombin itself stimulated expression of IL-6 and IL-8 to some degree and induced IL-6 production of SMC synergistically with IL-1. Platelets also induced proliferation of SMC, however, anti-PDGF antibodies, rather than IL-1-Ra blocked this response. These data show that platelet-derived IL-1 stimulates cytokine production of vascular smooth muscle cells, indicating that platelet-derived IL-1 may contribute to regulation of local pathogenesis in the vessel wall by activation of the cytokine regulatory network.
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PMID:Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. 941 77

We have previously shown that daily injection of alcohol for 3 days induced a significant and long-lasting blunting of the hypothalamic-pituitary-adrenal (HPA) axis response to a subsequent treatment with this drug. The fact that, in contrast, the HPA axis response to footshocks was not altered by prior alcohol administration, suggested the presence of a phenomenon of selective neuroendocrine tolerance. To further test this hypothesis, we determined whether an initial alcohol challenge would alter the ACTH response to immune signals, such as interleukin-1beta (IL-1beta) and/or endotoxin (lipopolysaccharide; LPS). Because of the functional connection between the HPA axis and immune responses, we also determined whether the LPS-induced release of tumor necrosis factor-alpha and interleukin-6, as well as IgG and IgM responses to an antigenic challenge, would be influenced by previous exposure to alcohol. We show here that the intragastric injection of 3 g of alcohol/kg daily for 3 days did not significantly alter the ability of IL-1beta (400 ng/kg) or LPS (1 microg/kg), both injected intravenously 7 days later, to release ACTH. Drug pretreatment did not significantly alter the tumor necrosis factor-alpha response to the low dose of endotoxin used, whereas there was a tendency toward increased circulating interleukin-6 levels in alcohol-pretreated animals. Finally the IgG, but not IgM, response to the antigen phosphocholine-keyhole limpet hemocyanin was significantly (p < 0.05) augmented in rats administered alcohol 7 days before the antigenic challenge. Collectively, these results indicate that an initial exposure to alcohol does not induce long-term changes in the ability of an immune signal (IL-1beta or endotoxin) to activate the HPA axis. In contrast, a small but detectable enhancement of cytokine responses to LPS, and of the IgG response to phosphocholine-keyhole limpet hemocyanin, was observed.
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PMID:Effect of pretreatment with alcohol on subsequent endocrine and immune responses in the adult male rat. 943 31

Following infection with influenza virus, animals display decreased locomotor activity and feeding behavior and loss of body weight. It has been suggested that these effects may be mediated by cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), induced by the infection. To assess the potential role of IL-1, we tested the ability of a naturally occurring IL-1-receptor antagonist (IL-1ra) to antagonize the changes in feeding behavior induced by IL-1, endotoxin (lipopolysaccharide, LPS), and infection with influenza virus. Feeding behavior was assessed by measuring the daily intake of food pellets and sweetened milk in a 30-min period. Acute injection of IL-1 beta decreased milk intake, but mouse IL-6 and mouse TNF-alpha did not. However, TNF-alpha decreased food pellet intake slightly, especially when it was injected at the beginning of the dark phase. The reductions in milk intake induced by mouse IL-1 beta were largely prevented by IL-1ra pretreatment (100 micrograms/mouse i.p.). The LPS-induced reductions in milk intake were attenuated, but not blocked, by IL-1ra treatment (300 micrograms/mouse). LPS still induced significant decrements in the presence of the antagonist. In influenza virus-infected mice, IL-1ra was administered either by repeated subcutaneous (s.c.) injections, or by continuous s.c. infusion from osmotic minipumps. These IL-1ra treatments produced small, but statistically significant, attenuations of the depression in milk and food pellet intake in the virus-infected mice. In several experiments, IL-1ra treatment increased the survival of influenza virus-infected mice. Thus the attenuation of the hypophagia may have been caused by this IL-1ra-induced increase in survival. The results suggest that IL-1 contributes to sickness behavior induced by LPS and influenza virus infection, but it is not the only factor involved.
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PMID:The role of cytokines in the behavioral responses to endotoxin and influenza virus infection in mice: effects of acute and chronic administration of the interleukin-1-receptor antagonist (IL-1ra). 943

Macrophages, predominant cells in dialysates of patients on CAPD without peritonitis, produce a wide variety of substances including cytokines. The aim of this study was to examine the cytokine production in five uninfected patients. This work investigated the presence in dialysates of interleukin-1beta, interleukin-6, interleukin-8, tumor necrosis factor alpha and the ability of peritoneal macrophages to produce these cytokines. These results were compared with values obtained from control group in non-uremic conditions (peritoneal lavage with isotonic saline or dialysis fluid). All cytokines were detectable in dialysates. Interindividual variations in cytokine concentration in dialysates were wider than variations of production of cytokines ex vivo by stimulated and unstimulated cells. In control group, dialysis fluid inhibited the cytokine production and with isotonic saline, cells produced less cytokines than dialysis patients' cells. The highest levels of interleukin-1 and tumor necrosis factor in dialysates and the highest capacity to respond to LPS were observed in patients having the shortest duration of dialysis. The variability observed did not seem to be due to cells themselves but to their environment.
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PMID:Variations of cytokine levels and production in CAPD patients. 946 71

The heavy metal lead (Pb) markedly augments the lethality of endotoxin in laboratory animals. Much of the tissue injury produced by endotoxin is thought to be mediated by cytokines. Thus, the effects of Pb on the regulation of interleukin-6 (IL-6), a proinflammatory cytokine that shows high correlation with symptoms of endotoxic shock, and the levels of corticosterone, a hormone produced to prepare the body to cope with stress, upon lipopolysaccharide (LPS; endotoxin) administration were investigated. After intravenous administration of LPS, the kinetics of IL-6 gene expression by Northern blot analysis revealed a rapid increase of IL-6 mRNA, which peaked by 2 h in the spleens and 3 h in the brains of B6C3F1 female mice, with or without Pb exposure. Peak production of IL-6 protein after LPS challenge was observed at 2 h in the spleens and 3 h in the sera regardless of Pb-treatment. However, Pb-exposed mice showed an altered kinetic profile of IL-6 appearance in the brain, in that the levels of IL-6 in the brains peaked at 4 h rather than 3 h, the peak for the control mice. Moreover, at two time points, the amounts of IL-6 were found to be higher in the brains of Pb-treated mice. Increases in IL-6 were detected in multiple areas of the brain, but Pb did not significantly enhance this level in any area. The observation of both IL-6 transcripts and protein in the brains of mice upon peripheral LPS administration is indicative of local de novo synthesis of IL-6 in the brain. IL-6 production in the brain may contribute to the centrally mediated effects of IL-6, since IL-6 in the brain is known to activate the hypothalamus-pituitary-adrenal (HPA) axis. Upon LPS challenge, corticosterone levels peaked at the 2-h time point and stayed elevated for 6 h regardless of Pb exposure. The increases in brain IL-6 and its extended expression by Pb do not appear to have significantly altered the HPA axis on the basis of the corticosterone level, but brain IL-6 is known to affect multiple brain functions such as long-term potentiation.
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PMID:Differential production of interleukin-6 in the brain and spleen of mice treated with lipopolysaccharide in the presence and absence of lead. 951 39

The interaction between lymphocytes, cytokines, and endothelial cells (EC) is a key step in the inflammatory process. Interleukin-6 (IL-6) a pleiotropic cytokine in its effects, seems to be an early indicator of acute systemic inflammation. In this study, we have examined the effects of polyunsaturated fatty acids (PUFAs) on the production of IL-6 by human unstimulated EC or EC stimulated with TNF-alpha (100 U/ml); IL-4 (100 U/ml); LPS (1 ug/ml); or allogeneic peripheral blood lymphocytes (PBL). Twenty-four hour culture supernatants of immunoreactive IL-6 were measured by Sandwich ELISA. We have shown that the production of IL-6 was potentiated when EC were stimulated with TNF-alpha; IL-4; LPS; or monocyte-depleted PBL in comparison to unstimulated EC. The addition of n-3 PUFAs in culture medium (100 ug/ml DHA or EPA) significantly reduces the production of IL-6 by unstimulated EC; or stimulated with TNF-alpha; IL-4 pg/ml); LPS or depleted PBL respectively for DHA and EPA, whereas the n-6 PUFAs (Arachidonic acid), even used at the highest concentration, was ineffective. This inhibitory effect is PUFA dose dependent but is more potent with EPA than DHA. Regardless of the mode of action, since IL-6 is known to be involved in hematopoiesis, in the regulation of the immune response and in the inflammatory reaction, these results suggest that n-3 PUFAs may play a role in suppressing inflammation. Further studies are needed to elucidate the mechanism involved and the choice between the two fatty acids for clinical and therapeutic purposes.
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PMID:Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6. 954 8

We have measured the transendothelial electrical resistance across the blood-brain barrier (BBB) with a microelectrode technique and determined the effects of subcutaneous injections (five injections over ten days) of lipopolysaccharide (LPS, 100 ng/g), recombinant mouse interleukin-6 (IL-6, 5 ng/g), and/or inorganic lead (lead, 2.5 5 micrograms/g) on the ion permeability of arterioles in the temporoparietal cortex of anaesthetized mice between 10 and 40 days of age. In controls the electrical resistance increased with age. It was decreased in animals treated with IL-6, but unaffected by lead at the different ages studied. In IL-6 treated mice, repeated neonatal exposure to lead (five injections between 2 and 10 days after birth) caused a delay in the increase in arteriole resistance with age. LPS injections caused a 36% increase in ion permeability of the BBB in twenty-day-old mice, and lead potentiated this effect of LPS. Intra-arterial injections of glutamate did not alter vascular resistance, but topical applications of glutamate on the cerebrum caused a reversible decrease in the resistance in mice not treated with lead, and an irreversible decrease in mice treated with lead. Injections of glutamate in the lumen of arterial vessels in the parietal and temporoparietal brain areas of mice pretreated with lead and LPS, plus a topical application of glutamate, caused depolarization of neurons in the temporoparietal cortex. These results suggest that disruption of the BBB can allow serum glutamate to penetrate the brain, causing further disruption of the BBB, and that lead irreversibly potentiates this cascade of harmful events.
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PMID:Lead potentiates cytokine- and glutamate-mediated increases in permeability of the blood-brain barrier. 955 65

The distribution of intracellular ionized lead (Pb) and calcium in dissociated cerebellar cells of ten-day-old mice was measured by flow cytometry. There are no fluorescent probes specific for lead, whereas commonly used fluorescent calcium indicators bind heavy metals with greater affinity than they do calcium, which impedes discrimination of lead- and calcium-induced fluorescence changes. Therefore, we developed a method to determine [Pb2+]i and [Ca2+]i by employing a combination of the calcium indicator fluo-3 and the heavy-metal chelator TPEN. Using these methods, we studied the effects of multiple in vivo exposure (five subcutaneous injections over 10 days) to lipopolysaccharide (LPS, 100 ng/g), recombinant mouse interleukin-6 (IL-6, 5 ng/g) and/or inorganic lead (lead, 2.5 micrograms/g) on lead and calcium concentrations. Control cells had [Cai] of 112 nM. Lead exposure alone had little effect on [Ca2+]i and resulted in a mean [Pb2+]i of about 7 pM, and did not alter cell volume. A significant fraction of cells (about 44% of living cells) from animals treated with lead plus LPS were swollen, as determined by analysis of the light scattering pattern, and there was a small increase in the number of dead cells, identified with the nucleic acid stain, 7-aminoactinomycin. While [Ca2+]i was not significantly increased in animals treated with either only LPS or IL-6, lead and calcium concentrations were increased in animals exposed to lead and LPS or IL-6 in both the non-swollen and swollen cells, with a mean value of (Pb2+)i of 32 pM and (Ca2+)i of 155 nM in cells not swollen. Electrophysiological analysis showed that LPS injections caused decreases in the membrane potential of endothelial cells of the blood-brain barrier (BBB) and lead potentiated the effect of LPS. IL-6 mimicked the effects of LPS, but was less potent. Thus these experiments indicate a synergistic interaction between lead and cytokines on biophysical properties of both neurons and endothelial cells of the BBB.
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PMID:Lipopolysaccharide and interleukin-6 enhance lead entry into cerebellar neurons: application of a new and sensitive flow cytometric technique to measure intracellular lead and calcium concentrations. 955 66

Vasoactive intestinal peptide (VIP) is a neuropeptide synthesized by immune cells that can modulate several immune aspects, including the function of cells involved in the inflammatory response, such as macrophages and monocytes. Production and release of cytokines by activated mononuclear phagocytes is an important event in the pathogenesis of ischemia-reperfusion injury. VIP has been shown to attenuate the deleterious consequences of this pathologic phenomenon. We have investigated the effects of VIP and PACAP38 on the production of interleukin-6 (IL-6), a proinflammatory cytokine, by endotoxin-activated murine macrophages. Both neuropeptides exhibit a dual effect on the IL-6 production by peritoneal macrophages. Whereas VIP and PACAP inhibit with similar dose-response curves the release of IL-6 from macrophages stimulated with a LPS dose range from 100 pg/mL to 10 microg/mL, both neuropeptides enhance IL-6 secretion in unstimulated macrophages and in macrophages stimulated with very low LPS concentrations (1-10 pg/mL). The inhibition on LPS-induced IL-6 production is specific, presumably mediated through a subtype of the PACAP-R. VIP and PACAP regulate the production of IL-6 at a transcriptional level. These results were correlated with an inhibition on both IL-6 expression and release in endotoxemic mice in vivo. These findings support the idea that in the absence of stimulation or in the presence of low doses of LPS, VIP and PACAP could play a role in immune system homeostasis. However, under toxicity conditions associated with high LPS doses, VIP and PACAP could act as protective mediators that regulate the excessive release of IL-6 in order to reduce inflammation or shock.
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PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide modulate endotoxin-induced IL-6 production by murine peritoneal macrophages. 958 3

Cytokines, such as tumor necrosis factor (TNF) and interleukin-6, may contribute to the anorexia and cachexia of infection, cancer, and AIDS. The present study tests the hypothesis that endotoxin alters the expression of two key fat cell proteins, leptin and beta3-adrenergic receptor (beta3-AR), through a mechanism involving TNF-alpha. Increasing doses of Escherichia coli endotoxin (lipopolysaccharide, LPS) resulted in dose-dependent elevations of plasma leptin (maximal response approximately 7-fold, half-maximal effective dose of approximately 16 microg/100 g body wt) and white fat leptin mRNA in C3/HeOUJ mice. LPS also produced a large decrease in adipose tissue beta3-AR mRNA and a parallel reduction in beta-agonist-induced activation of adenylyl cyclase. Changes in plasma leptin and beta3-AR mRNA were preceded by an approximately threefold increase in white fat TNF mRNA. TNF administration resulted in changes similar to those seen with LPS. We conclude that endotoxemia results in an induction of leptin mRNA and a decrease in beta3-AR mRNA in adipose tissue, an effect that may be mediated by alterations in TNF-alpha.
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PMID:Endotoxin-induced alteration in the expression of leptin and beta3-adrenergic receptor in adipose tissue. 961 Nov 47

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