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)

The effects of inflammatory cytokines (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha) on energy metabolism were studied in primary cultured rat hepatocytes. Adenine nucleotide (ATP, ADP, and AMP) content, lactate production, the ketone body ratio (acetoacetate/beta-hydroxybutyrate) reflecting the liver mitochondrial redox state (NAD+/NADH), and nitric oxide formation were measured. Insulin increased ATP content in hepatocytes and had a maximal effect after 8-12 h of culture. Both interleukin-1beta and interleukin-6, but not tumor necrosis factor-alpha, significantly inhibited the ATP increase time- and dose-dependently. Interleukin-1beta and interleukin-6 also stimulated lactate production. During the same period, interleukin-1beta but not interleukin-6 decreased the ketone body ratio. Furthermore, interleukin-1beta markedly stimulated nitric oxide formation in hepatocytes, and this increase was blocked by NG-monomethyl-L-arginine (a nitric oxide synthase inhibitor) and by interleukin-1 receptor antagonist. NG-monomethyl-L-arginine reversed inhibition of the ATP increase, decrease in the ketone body ratio, and increase in lactate production, which were induced by interleukin-1beta. Interleukin-1 receptor antagonist completely abolished all of the effects induced by interleukin-1beta. These results demonstrated that interleukin-1beta and interleukin-6 affect the insulin-induced energy metabolism in rat hepatocytes by different mechanisms. Specifically, interleukin-1beta inhibits ATP synthesis by causing the mitochondrial dysfunction, a process which may be mediated by nitric oxide.
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PMID:Regulation of energy metabolism by interleukin-1beta, but not by interleukin-6, is mediated by nitric oxide in primary cultured rat hepatocytes. 860 98

alpha-Melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide derived from pro-opiomelanocortin, has potent antiinflammatory activity in laboratory animals. alpha-MSH inhibits nitric oxide production by murine macrophages, an influence believed to reflect activation of an autocrine circuit in these cells, one that is based on production and release of alpha-MSH and subsequent stimulation of melanocortin receptors. We found that THP-1 cells, human monocytic cells, produced alpha-MSH; this production was increased by interleukin-6, tumor necrosis factor a, or concanavalin A. These cells also expressed the gene for the human alpha-MSH receptor MC1. Unlike murine macrophages, THP-1 cells produced little nitrite in response to interferon-gamma (IFN-gamma) and lipopolysaccharide, and a-MSH inhibited this production only slightly. However, production of neopterin, a presumed primate homologue of nitric oxide in lower animals, was increased in THP-1 cells stimulated with INF-gamma plus TNF-alpha and alpha-MSH significantly inhibited this production. The evidence indicates that an autocrine regulatory circuit based on alpha-MSH occurs in human monocyte/macrophages much as in murine macrophages. alpha-MSH-induced modulation of specific inflammatory mediators/cytotoxic agents appears to differ depending on the importance of the mediators in the myelomonocytic cells of different species.
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PMID:alpha-MSH production, receptors, and influence on neopterin in a human monocyte/macrophage cell line. 860 97

Rat neonatal mortality to endotoxin and age-related changes in adherent splenic cell mediator production in vitro were investigated. Neonatal rat pups, 24, 48, 96, and 216 h old or maternal adult rats were administered doses of Salmonella enteritidis endotoxin, (.024 mg to 7.5 mg/kg) and survival was monitored for 72 h. Mortality demonstrated high sensitivity (p < .05) of neonates to endotoxin (particularly 24 h old neonates). Endotoxin administration .6 mg/kg intracardiac) produced a 100% lethality in 24 h neonates (p < .05) versus 23% or less lethality in the 48 to 216 h old age group. Endotoxin administration (.4 mg/kg subcutaneous) also produced 100% lethality in 24 h old neonates compared with reduced mortality versus older age groups. Endotoxin in vitro stimulated (p < .05) adherent splenic cell thromboxane (TX)B2, interleukin-6, and nitrite production in most groups. Splenic cell nitrite production was higher (p > .05) in the 24 h old neonates, but lower in 48 h and 96 h old groups compared with maternal adults. Splenic cell TXB2 production was higher (p < .05) in the 24 h and 216 h old neonates relative to maternal adults. In conclusion, 24 h old rat pups are more susceptible to endotoxic shock than older age groups and adults, and exhibit altered production of the cellular mediators nitric oxide and TXB2.
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PMID:Age-related mortality and adherent splenic cell mediator production to endotoxin in the rat. 860 3

Proinflammatory cytokines play an important role in the depression of cytochrome P450 (CYP450)-dependent drug metabolism in mammals during inflammation and infection. Although much has been learned concerning the effects and mechanisms of cytokine-mediated suppression of CYP450, there is limited knowledge about how cytokines affect UDP glucuronosyl transferases (UDPGT). The aim of the present study was to investigate the effects and dose dependency of recombinant human proinflammatory cytokines on both CYP450- and UDPGT-dependent enzyme activities in primary cultures of pig hepatocytes. A possible role of nitric oxide in cytokine-induced suppression of enzyme activities was studied by incubating hepatocytes in the presence of N G-nitro-L-arginine (L-NAME), a competitive inhibitor of nitric oxide (NO) biosynthesis. Incubation of hepatocytes with interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) decreased both oxidation and glucuronidation activities dose dependently, in which the effects on glucuronidation activities were even more pronounced. IL-6 differed from IL-1alpha and TNF-alpha by inhibiting CYP450 and UDPFT more effectively after 24 hr of incubation, whereas the inhibition by IL-1alpha and TNF-alpha was more pronounced after 12 hr. Only at a concentration of 500 U/ml did interferon-gamma (IFN-ganna) inhibit CYP450 and UDPGT. The inhibition of CYP450 enzyme activities by cytokines was probably not due to the production of NO, because L-NAME totally blocked NO production but had no effect on the cytokine-induced suppression of CYP450 enzyme activities. However, there might be a role for NO in the decrease of glucuronidation by cytokines, as L-NAME slightly though significantly prevented the inhibition of glucuronidation.
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PMID:Suppression of cytochrome P450- and UDP glucuronosyl transferase-dependent enzyme activities by proinflammatory cytokines and possible role of nitric oxide in primary cultures of pig hepatocytes. 866 49

I propose that central nervous system endothelial cells are directly or indirectly responsible for the brain pathology in hepatic encephalopathy, and that this damage to the central nervous system is mediated by specific cytokines and nitric oxide which activate endothelial cells and thereby alter their cell functions. Liver diseases are conditions characterized by high circulating levels of cytokines, namely interleukin-1, interleukin-6 and tumor necrosis factor. Interactions between these cytokines and central nervous system endothelial cells may trigger a cascade of events including enhanced blood-brain barrier permeability, brain edema, astrocyte alterations and gliosis. Cytokine-induced production of nitrogen reactive molecules by endothelial cells themselves may also lead to further cellular damage and neuronal dysfunction. This hypothesis may explain several characteristics of hepatic encephalopathy including reversibility, disease progression and clinical features. It also suggests potential ways of intervention.
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PMID:The role of central nervous system endothelial cell activation in the pathogenesis of hepatic encephalopathy. 867 59

Apoptosis is an important cellular process by which superfluous or unwanted cells are deleted from an organism during tissue remodeling and differentiation. Recent studies have demonstrated the role of this programmed cell death or "controlled cell suicide" in the physiological function of an organism. Suppression of apoptosis increases the susceptibility of an individual to malignancy whereas uncontrolled cell death is associated with degenerative diseases. Normal development of both female and male gonads is characterized by massive cell death. More than 99% of ovarian follicles endowed at early life are destined to undergo apoptosis and the exhaustion of these follicles serves as a "clock" for female reproductive senescence. In the testis, up to 75% of male germ cells also undergo apoptosis, perhaps as a mechanism to delete superfluous or defective germ cells. Gonadal cell apoptosis provides valuable models to study hormonal regulation of apoptosis. In the ovary, gonadotropins, estrogens, growth hormone, growth factors (IGFI, EGF/TGF-alpha, basic FGF), cytokine (interleukin-1 beta) and nitric oxide act in concert to ensure the survival of preovulatory follicles. In contrast, androgens, interleukin-6 and gonadal GnRH-like peptide are apoptotic factors. Developmental studies further indicate that fractions of endowed follicles are recruited throughout the reproductive life whereas most of the primordial follicles are "arrested" at the initial stage of development for a prolonged time. Because a transcriptional factor WT1 is expressed in high levels in follicles at early stages of development and because WT1 over-expression represses the promoter activity of inhibin-alpha gene, this nuclear protein may be important in the maintenance of follicles at early stages of development. Once a cohort of follicles is recruited to grow, it is destined to undergo apoptosis unless rescued by survival factors. After puberty onset and under gonadotropin stimulation, some of the growing antral follicles are "selected" to continue their final maturation and secrete high levels of estrogens to trigger ovulation. Following repeated cycles of recruitment, atresia or ovulation, the follicle reserve is exhausted, thus signaling the onset of reproductive senescence. Although the somatic granulosa cell is the major cell type undergoing apoptosis in the ovary, the germ cells in the testis also exhibit signs of apoptotic cell demise. In the testis, gonadotropins and androgens act as survival factors whereas exposure to elevated temperature in cryptorchid testes increases apoptosis. In the seasonally breeding hamster model, photoperiod-entrained regression and recrudescence of testis tissue serves as a unique natural model of apoptosis. With recent advances in our understanding of the cellular mechanism of apoptosis, including the elucidation of the Ced9/bc12 and Ced3/ICE family of proteins, further investigation of gonadal apoptosis may lead to a better understanding of gonadal degenerative disorders (such as premature ovarian failure and oligospermia), reproductive senescence and tumorigenesis. The gonadal model should also be valuable in studying the regulation of intracellular apoptosis genes by external hormonal signals.
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PMID:Gonadal cell apoptosis. 870 Oct 90

Various plasma protein patterns following inflammation and metabolic stress were described since diagnostic value of ESR was established. This reactive dysproteinemia is now recognized to reflect the shift in hepatic proteosynthesis after the immunoendocrinological activation. Four main groups of mediators are necessary for expression of hepatic positive and negative acute phase proteins (APPs): first and second "wave' of proinflammatory cytokines, further glucocorticoids and growth factors including insulin. Actual data showing details of the immunological and endocrinological regulation of stress hepatocyte proteosynthesis are summarized and our own results are presented. We evaluated the diagnostic use of APPs in some defined clinical situations (neutropenic period after bone marrow transplantation, postoperative complications) and correlated APPs with the plasma levels of the circulating interleukin-6 and cortisol. In another study, APPs, plasma and urinary TNF, interleukin-6, interleukin-8 and adhesive molecules ICAM-1, VCAM-1 were found to be significantly different in various glomerulopathies. Finally, our experimental data indicate the nitric oxide participation in oestradiol regulation of coeruloplasmin synthesis in rat.
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PMID:[Acute phase proteins]. 871 1

Both nitric oxide and cytokines are considered mediators of the acute-phase response in humans, and their early postoperative period plasma levels have been found to be of prognostic value. On the other hand, it has been suggested that the fatty emulsions used in total parenteral nutrition (TPN) may induce changes in macrophage function. In the present study we investigated the postoperative evolution of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), and nitrate/nitrite plasma levels under three different TPN regimens. Twenty-one patients diagnosed with upper digestive tract neoplasm, without preoperative TPN, and having undergone radical surgery, were randomly assigned to three groups: Group I, all nonprotein calories supplied by hypertonic glucose solution: Group II, 55% of the nonprotein calories supplied by glucose and 45% by 20% long-chain triacylglycerides emulsion (LCT) (Intralipid 20%, Kabi-Pharmacia); Group III, same as Group II, but a 20% emulsion of a mixture of medium-chain and long-chain triacylglycerides (MCT/LCT) (Lipofundina MCT/LCT 20%, B. Braun) was used instead of LCT. Blood samples were obtained on postoperative Days 1-5 and 10, 3 h after ending the lipid infusion. In all the three groups IL-1, IL-6, and TNF-alpha levels rose after surgery, peaking at Day 2, whereas NO2/NO3 levels had their peak at Day 3. Day-to-day comparison of plasma levels of cytokines and NO2/NO3 between the investigated groups did not show any statistical significance. Differences between group means were not found when the areas under the curve over the first 5 postoperative days were compared (1.72 +/- 0.25, Group I; 1.88 +/- 0.34, Group II; and 2.52 +/- 0.50, Group III, for TNF-alpha; 1.79 +/- 0.12, Group I; 1.92 +/- 0.18, Group II; and 1.50 +/- 0.12, Group III, for NO2/NO3). We conclude that the different parenteral nutrition regimens studied do not evoke alterations in cytokine and NO2 + NO3 levels in the patient groups investigated in this study.
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PMID:NO2/NO3 and cytokine plasma profiles under different postoperative parenteral nutrition regimens. 872 88

beta-Amyloid protein (A beta) is the major component of the senile plaques in Alzheimer's disease (AD), and microglial cells have been shown to be closely associated with these plaques. However, the roles of A beta and microglial cells in pathogenesis of AD remain unclear. Incubation of rat microglial cells with A beta(1-40) caused a significant increase in nitrite, a stable metabolite of nitric oxide (NO), in culture media, while there was no detectable increase in nitrite in astrocyte-rich glial cells or cortical neurons after incubation with A beta(1-40). Nitrite production by microglial cells was also induced by A beta(1-42), but not A beta(25-35). An inhibitor of NO synthase, NG-monomethyl-L-arginine (NMMA), as well as dexamethasone and actinomycin D, dose-dependently inhibited this nitrite production. Among the various cytokines investigated such as interleukin-1, interleukin-6, tumor necrosis factor-alpha and interferon-gamma (IFN-gamma), only IFN-gamma markedly enhanced A beta-dependent nitrite production. Cultured cortical neurons were injured by microglial cells stimulated with A beta in a dose-dependent manner in the presence of IFN-gamma. Neurotoxicity caused by the A beta plus IFN-gamma-stimulated microglial cells was significantly attenuated by NMMA. Thus, although further investigations into the effect of A beta on human microglial cells are needed, it is likely that A beta-induced NO production by microglial cells is one mechanism of the neuronal death in AD.
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PMID:beta-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity. 878 1

The endocrine and immune systems are interrelated via a bidirectional network in which hormones modulate immune function and in turn, immune responses are reflected in endocrine changes. Stimulated immune cells produce cytokines and these substances have been shown to modulate the corticotroph, somatotroph, gonadotroph and thyreotroph axes. Interleukin-1, interleukin-6 and tumor necrosis factor alpha can either stimulate or inhibit the corticotroph axis by acting at all three levels, the hypothalamus, the pituitary gland and the adrenal glands. The hypothalamic effects of the cytokines are fast and mediated by the prostaglandins and by the nitric oxide (NO) pathway. In contrast, the cytokines at pituitary level have a slow onset of effect and their effects are not mediated by the prostaglandins or by the NO pathway. The immuno-neuroendocrine interactions are involved in numerous physiological and pathophysiological conditions. Thus, the interactions with the hypothalamo-pituitary-adrenal axis may represent an important feedback mechanism, through which the immune system by stimulating the production of immunosuppressive glucocorticoids avoids an overshoot of the inflammatory response.
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PMID:[Immuno-endocrine interactions at the hypothalamo-hypophyseal level]. 878 44


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