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)

Cytokines play a significant role in the regulation of Toxoplasma gondii in the central nervous system. Cytokine-activated microglia are important host defense cells in central nervous system infections. Recent evidence indicates that astrocytes can also be activated by cytokines to inhibit intracellular pathogens. In this study, we examined the effect of gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 on the growth of T. gondii in a primary murine astrocyte culture. Pretreatment of astrocytes with IFN-gamma resulted in 65% inhibition of T. gondii growth. Neither TNF-alpha, IL-1, nor IL-6 alone had any effect on T. gondii growth. IFN-gamma in combination with either TNF-alpha, IL-1, or IL-6 caused a 75 to 80% inhibition of growth. While nitric oxide was produced by astrocytes treated with these cytokines, inhibition of T. gondii growth was not reversed by the addition of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine. Furthermore, IFN-gamma in combination with IL-1, IL-6, or TNF-alpha also induced inhibition in astrocytes derived from syngeneic mice deficient in the enzyme inducible nitric oxide synthase. This finding suggests that the mechanism of cytokine inhibition is not nitric oxide mediated. Similarly, the addition of tryptophan had no effect on inhibition, indicating that the mechanism was not mediated via induction of the enzyme indoleamine 2, 3-dioxygenase. The mechanism of inhibition remains to be elucidated. Results from this study demonstrate that cytokine-activated astrocytes are capable of significantly inhibiting the growth of T. gondii. These data indicate that astrocytes may be important host defense cells in controlling toxoplasmosis in the brain.
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PMID:Effect of cytokines on growth of Toxoplasma gondii in murine astrocytes. 974 8

The aims of this study were to examine the plasma availability of tryptophan, the precursor of 5-hydroxytryptamine (5-HT), and serum cytokines, such as interleukin-6 (IL-6) and IL-8, in normal elderly volunteers and in patients with Alzheimer's disease (DAT). Elderly normal volunteers (mean age = 78.3 +/- 5.7 years) had a significantly lower tryptophan/competing amino acids (valine + leucine + isoleucine + phenylalanine + tyrosine) ratio than younger subjects (mean age = 32.9 +/- 8.1 years). In normal volunteers, there were significant and inverse relationships between age and either plasma tryptophan or the tryptophan/competing amino acids ratio, and between the availability of tryptophan to the brain and serum IL-6 or IL-8. DAT patients had significantly higher serum IL-6, but not IL-8, than age-matched normal volunteers. There were no significant differences in the availability of tryptophan to the brain between DAT patients and age-matched normal volunteers. The results suggest that: 1) in normal humans, the availability of plasma tryptophan to the brain decreases with age, and with activation of the immune system; and 2) increased production of IL-6 may play a role in the pathogenesis of DAT.
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PMID:Serotonin-immune interactions in elderly volunteers and in patients with Alzheimer's disease (DAT): lower plasma tryptophan availability to the brain in the elderly and increased serum interleukin-6 in DAT. 982 23

Interleukin-6 (IL-6) is one of several cytokines that can stimulate the hypothalamo-pituitary-adrenocortical (HPA) axis. Because IL-6 is produced in response to the administration of endotoxin (LPS) and interleukin-1 (IL-1), it is possible that IL-6 contributes to the neuroendocrine and neurochemical changes induced by them. In this study, intraperitoneal (i.p.) injection of LPS elevated plasma concentrations of IL-6 while activating the HPA axis in a dose-dependent manner. Both responses reached a peak at around 2-3 h. Mouse IL-1beta administration (100 ng, i.p.) induced large increases in plasma corticosterone and a substantial, but short-lived increase in plasma IL-6 with a peak at 2 h. Pretreatment of mice intraperitoneally with a monoclonal antibody to mouse IL-6 significantly attenuated the plasma ACTH and corticosterone responses to LPS at 3 h, but not at 1 h. Anti-IL-6 treatment also attenuated the LPS-induced increases of tryptophan and the serotonin catabolite, 5-hydroxyindoleacetic acid (5-HIAA), but not that of the norepinephrine catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG). Pretreatment of mice with anti-IL-6 significantly attenuated the IL-1-induced increases of plasma ACTH and corticosterone at 2 h, but not at 4 h. The IL-1-induced increases of MHPG, tryptophan and 5-HIAA in hypothalamus and brain stem were not significantly altered. These results suggest that IL-6 contributes to the later phases of the LPS- and IL-1-induced stimulations of the HPA axis and to the indoleaminergic responses to LPS, but not to IL-1.
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PMID:The role of interleukin-6 in the activation of the hypothalamo-pituitary-adrenocortical axis and brain indoleamines by endotoxin and interleukin-1 beta. 987 16

The transmembrane glycoprotein gp130 is the common signal transducing receptor subunit of the interleukin-6-type cytokines. It is a member of the cytokine-receptor superfamily predicted to consist of six domains in its extracellular part. The second and third domain constitute the cytokine-binding module defined by a set of four conserved cysteines and a WSXWS motif, respectively. The three-dimensional structure of the carboxy-terminal domain of this region was determined by multidimensional NMR. The domain consists of seven beta-strands constituting a fibronectin type III-like topology. The structure reveals that the WSDWS motif of gp130 is part of an extended tryptophan/arginine zipper which modulates the conformation of the CD loop.
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PMID:The signal transducer gp130: solution structure of the carboxy-terminal domain of the cytokine receptor homology region. 1021 Jan 78

Endotoxin (LPS) administration has been shown to activate the hypothalamo-pituitary-adrenocortical (HPA) axis and increase cerebral catecholamine and indolamine metabolism and tryptophan concentrations. LPS stimulates the secretion of tumor necrosis factor-alpha (TNF-alpha) as well as interleukin-1 and interleukin-6. We have investigated the role of TNF-alpha in the LPS-induced neurochemical and neuroendocrine changes. When recombinant mouse TNF-alpha (mTNF-alpha) was injected intraperitoneally (i.p.) into mice, plasma corticosterone concentrations were elevated reaching a peak at 30 min. Two hours after injection, cerebral tryptophan concentrations were also elevated in several brain regions, as well as the ratio of brain 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) to norepinephrine (NE) in the hypothalamus. An intravenous (i.v.) injection of mTNF-alpha also increased cerebral tryptophan concentrations and MHPG/NE ratios at 2 h and caused a rapid and prolonged elevation of plasma corticosterone concentrations lasting for at least 2 h. We observed no significant changes in dopamine or its catabolites, or in 5-hydroxytryptamine or its major catabolite, 5-hydroxyindoleacetic acid, after either i.p. or i.v. injections. These results suggest that TNF-alpha may contribute to the HPA, neurochemical and behavioral responses to LPS and other stimulators of the immune system.
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PMID:Mouse tumor necrosis factor-alpha increases brain tryptophan concentrations and norepinephrine metabolism while activating the HPA axis in mice. 1047 50

Biological activities of the multifunctional cytokine, interleukin-6 (IL-6) include stimulation of B cell proliferation, immunoglobulin production, and initiation of the acute-phase response. IL-6 affects the CNS in that it activates the hypothalamo-pituitary-adrenocortical (HPA) axis and increases brain tryptophan and serotonin metabolism. IL-6 has been proposed as an important mediator of interaction between the neuroendocrine and immune systems. The peripheral and central effects of IL-6 are presumably mediated through its membrane receptor (IL-6R). IL-6, IL-6R and their respective mRNAs have been detected in several brain regions. Although the functions of cytokines overlap considerably, each displays its own characteristic properties. Expression of IL-6 in the brain has been observed in several CNS disorders, some of which have been associated with disorders of serotonin metabolism. It is proposed that interactions between IL-6 and brain serotonin is a complex process which involves corticotropin-releasing factor (CRF) and opioid peptides. It is likely that the molecular mechanisms underlying the actions of IL-6 on the HPA axis and its other brain functions involve the integrated effects of glutamate, Ca2+, 3',5'-cyclic AMP, protein kinase C, and other metabolic pathways.
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PMID:Molecular mechanisms of actions of interleukin-6 on the brain, with special reference to serotonin and the hypothalamo-pituitary-adrenocortical axis. 1048 89

Reactive oxygen species are thought to be involved in the pathogenesis of septic multiple organ dysfunction syndrome (MODS). It has been reported that heme oxygenase-1 (HO-1) (EC 1.14.99.3) is induced in septic animal models and is thought to confer protection against oxidative tissue injury. In this study, we examined changes in gene expression of HO-1 and non-specific delta-aminolevulinate synthase (ALAS-N) (EC 2.3.1.37), the rate-limiting enzymes in heme catabolism and heme synthesis, respectively, after intraperitoneal administration of bacterial lipopolysaccharide (LPS) to rats. LPS treatment caused the elevation of body temperature, increases in white blood cell counts, and marked elevation of serum interleukin-6 levels associated with liver, lung, and kidney injuries, characteristic of septic MODS. LPS administration significantly induced HO-1 mRNA, protein, and enzyme activity in the liver, lung, and kidney. In contrast, ALAS-N mRNA was decreased rapidly in the liver, followed by an oscillating recovery pattern. Induction of hepatic HO-1 mRNA and rapid suppression of ALAS-N mRNA were likely the result of a rapid increase in hepatic free heme concentration as judged by the increase in heme saturation of tryptophan pyrrolase. In contrast to that in the liver, the ALAS-N mRNA level in the lung and kidney was increased significantly after LPS administration, suggesting a novel mechanism of ALAS-N regulation in these tissues. These findings suggest that HO-1 and ALAS-N mRNA are regulated in a tissue-specific manner in a rat model of septic MODS.
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PMID:Tissue-specific gene expression of heme oxygenase-1 (HO-1) and non-specific delta-aminolevulinate synthase (ALAS-N) in a rat model of septic multiple organ dysfunction syndrome. 1082 73

The potential contribution of stress-induced bacterial translocation to the activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and brain biogenic amines was assessed. Mice were restrained for various periods, and brain concentrations of tryptophan, catecholamines, serotonin, and their metabolites, plasma corticosterone, and the translocation of viable bacteria from the gastrointestinal tract to the mesenteric lymph nodes, spleen, and liver were measured. Restraint induced the translocation of indigenous gram-positive bacteria in only a small proportion of animals, but translocation of gram-negative bacteria did not occur. Restraint induced short-lived increases in plasma corticosterone and brain amine metabolism, whereas bacterial translocation was slower and persisted long after the HPA axis and neurochemical responses had dissipated. When mice were infected with Salmonella typhimurium, spontaneous translocation occurred and plasma corticosterone, interleukin-6 concentrations, and brain catecholamine and indoleamine metabolism were elevated. These findings indicate that the translocation of indigenous gastrointestinal bacteria did not contribute to the HPA axis and neurochemical changes induced by restraint. However, translocation of nonindigenous S. typhimurium with or without restraint did induce HPA and neurochemical responses.
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PMID:Bacterial translocation can increase plasma corticosterone and brain catecholamine and indoleamine metabolism. 1108 82

Previous studies have indicated that peripheral administration of interleukin-6 (IL-6) increases brain concentrations of tryptophan and 5-hydroxyindoleacetic acid (5-HIAA), the major catabolite of serotonin (5-HT). To determine whether these changes were related to increased synaptic release of 5-HT, we studied the responses to peripheral administration of IL-6 by in vivo microdialysis and in vivo amperometry. Intraperitoneal injection of recombinant IL-6 resulted in an elevation of microdialysate concentrations of 5-HT in the rat striatum. Also, amperometric measurements indicated that i.p. IL-6 enhanced the 5-HT-like signal obtained from the striatum following electrical stimulation of the dorsal raphe nucleus. These results indicate that the increases in brain concentrations of 5-HIAA observed in earlier studies indeed reflect increased synaptic release of 5-HT.
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PMID:Peripheral interleukin-6 administration increases extracellular concentrations of serotonin and the evoked release of serotonin in the rat striatum. 1113 24

The observation that administration of interleukin-1 (IL-1) to animals activates the hypothalamo-pituitary-adrenocortical (HPA) axis stimulated great interest in the significance and mechanism of this response, and in whether other cytokines have similar activities. Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) share HPA-activating activity, although they are less potent and effective than IL-1, whereas IL-2 and interferon alpha(IFN alpha) lack activity. Small increases in body temperature occur in response to IL-1, IL-6 and TNF alpha, but these changes are prevented by inhibitors of cyclooxygenase (COX) and do not appear to be related to the HPA-activation. The rapid HPA-activating effects of IL-1 are impaired by COX inhibitors, but the more prolonged HPA activation associated with intraperitoneal injections is not affected, indicating multiple mechanisms for IL-1-induced HPA activation. The HPA response to IL-6 is not sensitive to COX inhibitors, but that to TNF alpha appears to be. The HPA-activating activity of IL-1 is associated with increases in the apparent release of brain noradrenaline (NA) and serotonin (5-HT), but not dopamine, as well as with increased brain tryptophan. The NA changes, but not these in serotonin metabolism and tryptophan, are prevented by COX inhibitors. IL-6 has effects on serotonin and tryptophan like those of IL-1, but no detected effect on NA. TNF alpha has some effect on NA and tryptophan, but only at relatively high doses. IFN alpha lacks activity on these neurochemicals. Manipulation of noradrenergic, but not serotonergic systems alters the IL-1-induced HPA activation, suggesting the involvement of NA. However, brain NA does not appear to be essential for HPA activation in mice.
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PMID:Cytokine activation of the HPA axis. 1126 89


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