UNIPROT:P05231 - FACTA Search

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

In ovarian cancer patients the poor nutritional status and cachexia are caused by the metabolic effects of the enlarging tumor masses and bowel obstruction. These patients may have a high resting energy expenditure due to increase in Cori cycle activity, glucose and triglyceride-fatty acid cycling and gluconeogenesis. Biochemical mediators of cachexia include cytokines, such as tumor necrosis factor and interleukin-6, and tumor-produced catabolic factors, such as lipid-mobilizing factor, proteolysis-inducing factor, and anemia-inducing factor. Mechanisms involved in the pathogenesis of obstruction may include extrinsic occlusion of the bowel due to pelvic, mesenteric omental masses, or intestinal motility disorders due to infilor tration of the mesentery or bowel muscle and nerves. The relief of malnutrition and cachexia may be attempted through nutritional support, pharmacological approach (megestrol acetate, cyclooxygenase inhibitors) and palliative treatment of bowel obstruction. Very few agents have been demonstrated to have true anticachectic activity, so future research should be addressed to the identification of drugs able to block the activity of tumor-produced catabolic factors. The decision regarding optimum management of bowel obstruction should be individualized. Krebs' and Goplerud's score (based on age, nutritional status, tumor status, ascites, previous chemotherapy and irradiation) seems to offer reliable eligibility criteria for those patients who can benefit from surgery.
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PMID:Malnutrition and cachexia in ovarian cancer patients: pathophysiology and management. 1171 91

We have previously reported that long-term treatment with clarithromycin (CAM) increased the median survival of patients with non-small cell lung cancer, and improved various clinical parameters in these patients. In the present study, CAM was administered to 33 patients with unresectable primary non-small cell lung cancer, who had received chemotherapy, radiotherapy or both (basic cancer therapy). Patients with clinical backgrounds matched to the CAM group, who did not receive CAM treatment, were included into this study as a control group (non-CAM group). CAM treatment was initiated 4 weeks after the basic cancer therapy. The non-CAM group did not receive a placebo. Before and after the 3-month treatment with CAM, body weight, serum levels of interleukin-6 (IL-6, a cytokine which, together with TNF-alpha, plays a crucial role in the development of cancer cachexia), total protein, albumin, cholinesterase and hemoglobin were measured for the evaluation of the patients' clinical status. There were no statistically significant differences in serum levels of IL-6 between the CAM group before the treatment and the non-CAM group. After 3 months of CAM treatment, serum levels of IL-6 significantly decreased. In contrast, body weight, cholinesterase, and hemoglobin increased to a significant extent. Among these four parameters, however, the decrease in serum IL-6 levels was only statistically correlated with the increase in body weight, but not with that in other parameters. Furthermore, CAM-treated patients whose serum IL-6 levels were decreased after 3 months of treatment survived longer: there was a statistically significant correlation between the decrease in serum IL-6 and survival time. In contrast, in the non-CAM group, these parameters did not change significantly during the study. These results suggest that CAM may reduce the progression of cancer-associated cachexia.
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PMID:Anti-cachectic effect of clarithromycin for patients with unresectable non-small cell lung cancer. 1178 60

Under normal conditions, the homeostasis of energy intake is maintained in the hypothalamus by 1) transducing metabolic and sensorial inputs arising from the periphery into neuronal response, 2) integrating the information originating from different tissues, and 3) triggering the appropriate feeding responses. If cancer anorexia is considered a disruption of the physiologic mechanisms controlling energy intake, it is conceivable that its pathogenesis may lie in an abnormal input of information to the hypothalamus, its defective transduction and integration, or the induction of exaggerated and inappropriate feeding responses. Currently available data suggest that the pathogenesis of cancer anorexia is multifactorial and involves most of the neuronal signaling pathways modulating energy intake. Thus, a number of factors has been proposed as putative mediators of cancer anorexia, including hormones (e.g., leptin), neuropeptides (e.g., neuropeptide Y), cytokines (e.g., interleukin-1, interleukin-6, tumor necrosis factor), and neurotransmitters (e.g., serotonin and dopamine). However, it is unlikely that they represent separate and distinct pathogenic mechanisms; rather, it appears that close interrelationships may exist among them. In line with this reasoning, consistent experimental and human data suggest that hypothalamic monoaminergic neurotransmission and serotonergic activity in particular may represent a major target on which different anorexia-related factors converge. Thus, interfering pharmacologically with hypothalamic serotonin synthesis and activity has been tested as a therapeutic strategy in anorectic cancer patients with encouraging results. However, more clinical options will be available by revealing the complex interactions between the many factors participating in controlling energy intake under normal and pathologic conditions. Further, modulation of hypothalamic activity also might result in reduced catabolic signals to skeletal muscles, thus improving the cachexia associated with cancer.
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PMID:Neurochemical mechanisms for cancer anorexia. 1182 80

In vivo studies have shown that cancer-associated skeletal muscle wasting (cachexia) is mediated by two cytokines, tumor necrosis factor-alpha (TNF) and interleukin-6 (IL-6). It has been unclear from these studies whether TNF exerts direct effects on skeletal muscle and/or whether these effects are mediated via IL-6. Previous studies from our laboratory have shown that TNF induces IL-6 mRNA expression in cultured skeletal muscle cells. To further investigate the relationship between TNF and IL-6, the effects of TNF and IL-6 on protein and DNA dynamics in murine C2C12 skeletal myotube cultures were determined. At 1000 U/ml, TNF induced 30% increases in protein and DNA content. The effects of TNF on protein accumulation were inhibited by aphidicolin, an inhibitor of DNA synthesis. IL-6 mimicked the effects of TNF on C2C12 cultures, inducing a 32% increase in protein accumulation and a 71% increase in the rate of protein synthesis. IL-6 also decreased expression of mRNA for several proteolytic system components, including ubiquitin 2.4 kb (51%) and 1.2 kb (63%), cathepsin B (39%) and m-calpain (47%), indicating that IL-6 acts on both protein synthesis and degradation. Incubation of murine C2C12 myotube cultures with TNF (1000 U/ml) in the presence of a polyclonal mouse anti-IL-6 antibody resulted in an abolishment of the effects of TNF on protein synthesis, but did not inhibit TNF-induced stimulation of DNA synthesis. These findings indicate that the effects of TNF on muscle protein synthesis are mediated by IL-6, but that TNF exerts IL-6-independent effects on proliferation of murine skeletal myoblasts.
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PMID:Tumor necrosis factor-alpha exerts interleukin-6-dependent and -independent effects on cultured skeletal muscle cells. 1185 80

C-reactive protein (CRP) is a nonspecific but sensitive marker of inflammation. Interleukin-6 (IL-6), IL-1, and tumor necrosis factor alpha induce the synthesis of CRP in hepatocytes. Increased CRP level is considered to be an important risk factor for atherosclerosis, myocardial infarction, peripheral vascular disease, and ischemic stroke. It is positively correlated with weight loss, anorexia-cachexia syndrome, extent of disease, and recurrence in advanced cancer. Its role as a predictor of survival has been shown in multiple myeloma, melanoma, lymphoma, ovarian, renal, pancreatic, and gastrointestinal tumors. Measurement of CRP is simple, cheap, and routine and provides valuable information in palliative care.
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PMID:The role of C-reactive protein as a prognostic indicator in advanced cancer. 1193 16

Interleukin-6 (IL-6) is a multifunctional cytokine that activates the signaling pathways of Janus kinases-signal transducers and activators of transcription (STAT) and/or mitogen-activated protein kinases (MAPK) in various tumors. Thus, it modulates cell growth and apoptosis. IL-6 levels are elevated in tissues and sera from prostate cancer patients and IL-6 receptor expression has been detected in prostate cancer cell lines and clinical specimens. Continuous exposure of prostate cancer cells to IL-6 might alter their responsiveness to this cytokine. To gain more insight into the function of IL-6 in prostate carcinoma, we have inoculated LNCaP-IL-6+ cells, generated after prolonged treatment with IL-6, into nude mice (total n = 16, two independent experiments). Controls included animals bearing LNCaP-IL-6- cells, passaged at the same time as LNCaP-IL-6+ cells without supplementation of IL-6. LNCaP-IL-6+ tumor volumes were larger than those of their counterparts at all time points. There were no signs of cachexia in any of the experimental animals and all mice were free of metastases. To better understand the mechanisms responsible for accelerated growth of LNCaP-IL-6+ tumors, we have investigated the expression of cell-cycle regulatory molecules by Western blot analysis. The levels of cyclin-dependent kinase 2 were elevated in LNCaP-IL-6+ cells. There was a strong down-regulation of cyclins D1 and E in the LNCaP-IL-6+ subline. The cell-cycle inhibitor p27 was expressed at a low level in LNCaP-IL-6+ cells and could not be up-regulated by addition of IL-6. Most notably, LNCaP-IL-6+ cells exhibited a reduced expression of the hypophosphorylated form of the retinoblastoma protein (pRb). Accelerated tumor growth in our model system was also associated with alterations in IL-6-signaling pathways. The ability of IL-6 to induce tyrosine phosphorylation of STAT3 was abolished in the LNCaP-IL-6+ subline. In contrast, the levels of the MAPK extracellular signal-regulated kinases 1/2 increased in cells generated after long-term IL-6 treatment. The inhibitor of MAPK kinase PD 98059 retarded the proliferation of LNCaP-IL-6+ but not that of control cells. In summary, we show in the present study that chronic exposure of prostate cancer cells to IL-6 facilitates tumor growth in vivo by abolishment of the growth control by pRb and activation of the MAPK signaling pathway. These findings could be relevant to understand the role of IL-6 in prostate cancer progression.
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PMID:Accelerated in vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expression and activation of the mitogen-activated protein kinase pathway. 1254 23

Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. J., Klover, P. J., Nowak, I. A., and Mooney, R. A. (2002) Diabetes 51, 3391-3399). Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. Since several SOCS proteins are induced by IL-6, a working hypothesis is that IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS protein(s) in insulin target cells. To examine the involvement of SOCS protein(s) in IL-6-dependent inhibition of insulin receptor signaling, HepG2 cells were treated with IL-6 (20 ng/ml) for periods from 1 min to 8 h. IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. SOCS-3 protein levels were also markedly elevated at 1 h. Transcript and protein levels returned to near basal levels by 2 h. SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. Ectopically expressed SOCS-3 associated with the IR and suppressed insulin-dependent receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, and activation of Akt. SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance.
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PMID:Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. 1256 Mar 30

Elevated levels of proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-6 (IL-6), have been demonstrated in patients with chronic heart failure (CHF). Evidence suggests that cytokines such as these may play a central role in the pathogenesis of this syndrome. TNF has several properties that are particularly detrimental in CHF, such as negatively inotropic effects, the promotion of left ventricular remodelling, and the induction of dilated cardiomyopathy in humans. Furthermore, TNF can cause skeletal muscle wasting and apoptosis, and, therefore, may be important in the development of cardiac cachexia. Although the precise stimulus for immune activation in CHF is unknown, one hypothesis is that endotoxin may be a significant trigger for cytokine release. This is supported by the finding that decompensated CHF patients have elevated endotoxin levels that normalize on diuretic therapy. The factors that influence endotoxin responsiveness in patients with CHF, in particular the potential importance of serum lipoproteins, will be discussed in this review.
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PMID:The importance of tumor necrosis factor and lipoproteins in the pathogenesis of chronic heart failure. 1263 90

Recent studies have suggested that circulating concentrations of leptin might play a role in cancer cachexia. In the first part of the study, we compared circulating concentrations of free and total leptin, percent fat mass, and the inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6), together with appetite score, in age- and gender-matched healthy controls (n = 11) and advanced gastrointestinal cancer patients (n = 26). In the second part of the study, the same measurements were repeated before and after megestrol acetate treatment of weight-losing gastrointestinal cancer patients (n = 10). Body mass index and percent fat mass were significantly lower (P < 0.05) and IL-6 and CRP were significantly higher (P < 0.05) in cancer patients than in controls. There was no difference in the percentage of leptin bound in the circulation between controls and cancer patients. Circulating "free" leptin concentrations correlated with percent fat mass in controls (r = 0.745, P = 0.008) and cancer patients (r = 0.600, P = 0.001). In cancer patients, circulating leptin concentrations, either free or total, were not correlated with IL-6 or CRP concentrations. When adjusted for fat mass, the circulating concentrations of free and total leptin were significantly lower in the cancer patients (P < 0.01). Megestrol acetate treatment significantly increased circulating free and total leptin concentrations in the cancer patients (P < 0.05). There was a significant positive correlation between the change in circulating concentrations of free and total leptin and the change in percent fat mass (r = 0.685, P < 0.05 and r = 0.661, P < 0.05, respectively). The results of the present study indicate that the proportions of free and bound leptin in the circulation do not differ between normal subjects and patients with gastrointestinal cancer and in both groups are related to fat mass. Furthermore, the increase in circulating leptin concentrations after megestrol acetate treatment is not associated with any alteration in leptin binding.
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PMID:Circulating concentrations of "free" leptin in relation to fat mass and appetite in gastrointestinal cancer patients. 1273 62

Anorexia nervosa (AN) is a serious eating disorder characterized by extreme weight loss and abnormalities of the neuroendocrine and immune systems. Cytokines have been discussed to be involved in the pathomechanisms underlying cachexia. Therefore our study aimed at examining the mRNA expression pattern of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-6 (IL-6) and interleukin-10 (IL-10) in whole blood of 11 female AN patients and 10 age and sex matched normal weight control subjects using a sensitive quantitative polymerase chain reaction (PCR) method. We found a significant increase in TNF-alpha and IL-6 mRNA expression in anorectic patients at admission (mean BMI 14.8 +/- 1.3) when compared to controls. During follow-up, the expression of TNF-alpha mRNA remained significantly higher in formerly anorectic patients (mean BMI 18.7 +/- 0.5) while IL-6 mRNA expression decreased. We interpret our results as suggesting that TNF-alpha may contribute to metabolic abnormalities in anorexia nervosa even after goal BMI is achieved.
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PMID:Cytokine mRNA expression patterns in the disease course of female adolescents with anorexia nervosa. 1457 26

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