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)

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

Transcription factors belonging to the CCAAT-enhancer binding protein (C/EBP) family have been implicated in the regulation of gene expression during growth, differentiation, apoptosis, and inflammation. Autoregulation is relatively common in the modulation of C/EBP gene expression and, for the human and murine C/EBPalpha, it is known that species-specific autoregulatory mechanisms operate. It is therefore essential to investigate the autoregulation of additional C/EBP genes from a wider range of different species to gauge the degree of commonality, or otherwise, which exists. As an important step towards this goal, we report here the cloning and the characterisation of the ovine C/EBPdelta gene (ovC/EBPdelta) and analysis of its promoter region. Transient transfection assays reveal that ovC/EBPdelta acts as a transcriptional activator. Although several motifs that are characteristic of C/EBPdelta genes are conserved in the ovine sequence, including the basic region, leucine zipper, and activation domains, two regions have been identified that are specifically absent in the ovine and bovine homologues. The ovC/EBPdelta promoter is active in both the hepatoma Hep3B and the mammary epithelial HC11 cell lines, induced by the cytokine interleukin-6 and autoregulated by mechanisms that are potentially different from those described for the rat promoter. These results suggest that, in common with C/EBPalpha, the C/EBPdelta genes may also be subject to autoregulation by distinct species-specific mechanisms.
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PMID:The ovine CCAAT-enhancer binding protein delta gene: cloning, characterization, and species-specific autoregulation. 1079

The increased interest of using ultrafiltration during cardiopulmonary bypass ICPB) has mandated a re-evaluation of the hematological effects of this blood conservation process. 'Rinse-free' ultrafiltrators can be primed using either crystalloid or blood prior to use. It is unknown whether one priming technique results in superior results in ultrafiltration quality. An in vitro circuit was designed to evaluate the Sorin/COBE HC1400 (n=6), the Lifestream HC70 (n=6), and the Terumo/Sarns HC11 (n=6). All test conditions were conducted at a blood flow rate of 250 ml/min and a transmembrane pressure of 250 mmHg. Samples were drawn and analyzed at four distinct time points for hematocrit, total protein, plasma free hemoglobin, interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNFalpha). The HC11 had significantly greater percent increases in hematocrit under the blood priming protocol (29.2+/-7.9) than either the HC1400 (11.0+/-7.8, p<0.03) or the HC70 (11.9+/-7.8, p<0.04). When crystalloid priming was compared to blood priming, the HC1400 and HC70 produced significant percent increases in hematocrit and total protein levels. The HC1400 devices produced significantly less plasma free hemoglobin when primed with crystalloid rather than blood (43.6+/-38.3 vs 21.3+/-5.6, p<0.01). There were no significant differences between devices or priming techniques for IL-6, IL-8 or TNFalpha levels. In conclusion, the efficiency of the ultrafiltrators was elevated when primed with crystalloid before use. Cytokine levels were relatively unchanged with priming techniques, while plasma free hemoglobin levels were reduced with those devices previously primed with crystalloid.
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PMID:The effect of priming techniques of ultrafiltrators on blood rheology: an in vitro evaluation. 1141 58

Long-term arsenic exposure is associated with an increased risk of vascular diseases including ischemic heart disease, cerebrovascular disease, and carotid atherosclerosis. The pathogenic mechanisms of arsenic atherogenicity are not completely clear. A fundamental role for inflammation in atherosclerosis and its complications has become appreciated recently. To investigate molecular targets of inflammatory pathway possibly involved in arsenic-associated atherosclerosis, we conducted an exploratory study using cDNA microarray and enzyme-linked immunosorbent assay to identify genes with differential expression in arsenic-exposed yet apparently healthy individuals. As an initial experiment, array hybridization was performed with mRNA isolated from activated lymphocytes of 24 study subjects with low (0-4.32 microg/L), intermediate (4.64-9.00 microg/L), and high (9.60-46.5 microg/L) levels of blood arsenic, with each group comprising eight age-, sex-, and smoking frequency-matched individuals. A total of 708 transcripts of known human genes were analyzed, and 62 transcripts (8.8%) showed significant differences in the intermediate or high-arsenic groups compared with the low-level arsenic group. Among the significantly altered genes, several cytokines and growth factors involving inflammation, including interleukin-1 beta, interleukin-6, chemokine C-C motif ligand 2/monocyte chemotactic protein-1 (CCL2/MCP1), chemokine C-X-C motif ligand 1/growth-related oncogene alpha, chemokine C-X-C motif ligand 2/growth-related oncogene beta, CD14 antigen, and matrix metalloproteinase 1 (interstitial collagenase) were upregulated in persons with increased arsenic exposure. Multivariate analyses on 64 study subjects of varying arsenic exposure levels showed that the association of CCL2/MCP1 plasma protein level with blood arsenic remained significant after adjustment for other risk factors of cardiovascular diseases. The results of this gene expression study indicate that the expression of inflammatory molecules may be increased in human subjects after prolonged exposure to arsenic, which might be a contributory factor to the high risk of atherosclerosis in arseniasis-endemic areas in Taiwan. Further multidisciplinary studies, including molecular epidemiologic investigations, are needed to elucidate the role of arsenic-associated inflammation in the development of atherosclerosis and subsequent cardiovascular disease.
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PMID:Gene expression of inflammatory molecules in circulating lymphocytes from arsenic-exposed human subjects. 1292 51

During neuropathological conditions, high concentrations of adenosine are released, stimulating adenosine receptors in neurons and glial cells. It has recently been shown that stimulation of adenosine receptors in glial cells induces the release of neuroprotective substances such as NGF, S-100beta, and interleukin-6 (IL-6). It has therefore been suggested that glial adenosine receptors are involved in neuroprotection. Since recently neuroprotective effects of the chemokine CCL2 (formerly known as MCP-1) have been reported, we investigated the possible effect of adenosine receptor stimulation on glial CCL2 synthesis. Here we show that stimulation of cultured murine astrocytes with the selective adenosine A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine (CL-IB-MECA) induced the release of CCL2. Specific ligands for adenosine A1 or A2 receptors did not affect CCL2 release. Furthermore, CL-IB-MECA-induced CCL2 synthesis was inhibited by adenosine A3 receptor antagonists. These results show that stimulation of adenosine A3 receptors in astrocytes induced the release of CCL2, thus supporting the assumption that adenosine receptors in glial cells regulate the synthesis of neuroprotective substances.
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PMID:Adenosine A3 receptor-induced CCL2 synthesis in cultured mouse astrocytes. 1509 71

Leptin and its receptors have been shown to be expressed in several tissues, suggesting that this protein might be effective not only at the CNS level but also peripherally. We have previously reported that leptin and its long form receptor are expressed in the mouse mammary epithelial cell line HC11. In this study, we report a specific relationship among leptin, prolactin (PRL), interleukin-6 (IL-6), and tumor necrosis-alpha (TNF-alpha) in the modulation of the suppressor of cytokine signaling 1 (SOCS-1). Furthermore, we show that leptin and PRL are able to effectively enhance SOCS-1 gene expression in the HC11 cell line. Finally, high concentrations of leptin (100 nM) and/or PRL significantly (p<0.05) reduce the inhibitory effect of IL-6 (10 and 100 ng/ml) and TNF-alpha (10 and 100 ng/ml) on beta-casein gene expression in HC11 cells transfected with pbetacCAT, a chimeric rat-beta casein gene promoter-cloramphenicol acetyl transferase (CAT) gene construct. These results provide evidence that leptin may be an important mediator in regulating mammary gland growth and development and that this role may be related to the immune factors that are involved in inflammation.
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PMID:Leptin and prolactin modulate the expression of SOCS-1 in association with interleukin-6 and tumor necrosis factor-alpha in mammary cells: a role in differentiated secretory epithelium. 1525 87

Statins exert favorable effects on lipoprotein metabolism but may also possess anti-inflammatory effects. Here, we explored the effects of atorvastatin in a model of adjuvant-induced arthritis in rat. Oral treatment with atorvastatin (1-10 mg/kg) from days 10 to 15 after arthritis induction caused inhibition of the increase in paw volume. Maximal inhibition occurred at a dose of 10 mg/kg. At this dose, atorvastatin markedly ameliorated the histopathological findings of joints obtained from day 16 of arthritic animals. This was mirrored by an effective blockade of neutrophil influx, as assessed by the tissue myeloperoxidase levels. The concentrations of the cytokines interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha and the chemokines CCL5 and CCL2 were significantly decreased in arthritic rats treated with atorvastatin. In contrast, the levels of interleukin-10 were enhanced by the drug treatment. The drug also prevented the hypernociception observed in the inflamed joints. These data clearly illustrate the therapeutic potential of a statin-sensitive pathway in inflammatory arthritis.
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PMID:Anti-inflammatory and analgesic effects of atorvastatin in a rat model of adjuvant-induced arthritis. 1597 Feb 84

Chronic allograft nephropathy is characterized by chronic inflammation and fibrosis. Because retinoids exhibit anti-proliferative, anti-inflammatory, and anti-fibrotic functions, the effects of low and high doses of 13-cis-retinoic acid (13cRA) were studied in a chronic Fisher344-->Lewis transplantation model. In 13cRA animals, independent of dose (2 or 20 mg/kg body weight/day) and start (0 or 14 days after transplantation) of 13cRA administration, serum creatinine was significantly lower and chronic rejection damage was dramatically reduced, including subendothelial fibrosis of preglomerular vessels and chronic tubulointerstitial damage. The number of infiltrating mononuclear cells and their proliferative activity were significantly diminished. The mRNA expression of chemokines (MCP-1/CCL2, MIP-1alpha/CCL3, IP-10/CXCL10, RANTES/CCL5) and proteins associated with fibrosis (plasminogen activator inhibitor-1, transforming growth factor-beta1, and collagens I and III) were strikingly lower in treated allografts. In vitro, activated peritoneal macrophages of 13cRA-treated rats showed a pronounced decrease in protein secretion of inflammatory cytokines (eg, tumor necrosis factor-alpha, interleukin-6). The suppression of the proinflammatory chemokine RANTES/CCL5 x 13cRA in fibroblasts could be mapped to a promoter module comprising IRF-1 and nuclear factor-kappaB binding elements, but direct binding of retinoid receptors to promoter elements could be excluded. In summary, 13cRA acted as a potent immunosuppressive and anti-fibrotic agent able to prevent and inhibit progression of chronic allograft nephropathy.
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PMID:13-cis retinoic acid inhibits development and progression of chronic allograft nephropathy. 1597 72

Salmonella enterica is a gram-negative intracellular pathogen that can cause a variety of diseases ranging from gastroenteritis to typhoid fever. The Typhimurium serotype causes gastroenteritis in humans; however, infection of mice results in an enteric fever that resembles human typhoid fever and has been used as a model for typhoid fever. The present study examined the role of the chemokine CCL2 in the control of Salmonella infection. Upon infection with salmonellae, mucosal expression of CCL2 is rapidly up-regulated, followed by systemic expression in the spleen. CCL2(-/-) mice became moribund earlier and had a higher rate of mortality compared to wild-type C57BL/6 mice. Moreover, CCL2(-/-) mice had significantly higher levels of bacteria in the liver compared to wild-type controls. Mucosal and serum interleukin-6 and tumor necrosis factor alpha levels were elevated in CCL2(-/-) mice compared to wild-type mice. In vitro analysis demonstrated that CCL2(-/-) macrophages infected with salmonellae resulted in dysregulated cytokine production compared to macrophages derived from wild-type mice. These data are the first to directly demonstrate CCL2 as a critical factor for immune responses and survival following S. enterica infection.
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PMID:The chemokine CCL2 is required for control of murine gastric Salmonella enterica infection. 1617 25

Increasing data from epidemiological and in vitro studies show that the isoflavonoids, genistein and daidzein, and the flavonols, quercetin and kaempferol, are protective against postmenopausal bone loss. However, the physiological mechanisms for these effects are not well understood. We now report that kaempferol exerts profound antiosteoclastogenic effects by acting on both osteoblasts and osteoclasts. Kaempferol but not quercetin dose-dependently inhibited tumor necrosis factor alpha (TNFalpha)-induced production of the osteoclastogenic cytokines interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1/CCL2) in osteoblasts. The effect on IL-6 was posttranscriptional, whereas kaempferol reduced MCP-1 mRNA levels. In addition, in mouse primary calvarial osteoblasts, kaempferol but not quercetin blocked TNFalpha-induced translocation of the nuclear factor kappaB (NF-kappaB) subunit p65 from the cytoplasm to the nucleus. However, TNFalpha-stimulated intracellular ROS production was unaltered by kaempferol. In RAW264.7 cells, a monocyte/macrophage precursor for osteoclasts, both kaempferol and quercetin dose-dependently inhibited the receptor activator of NF-kappaB ligand (RANKL)-induced immediate-early oncogene c-fos expression at 6 h. After 3-5 days, both flavonols robustly inhibited RANKL-induced expression of the osteoclastic differentiation markers, RANK and calcitonin receptor. Consistent with down regulation of these osteoclastic differentiation markers, both flavonols strongly attenuated the RANKL-induced formation of multinucleated osteoclasts. However, kaempferol was more potent than quercetin in inhibiting RANKL-stimulated effects on RAW264.7 cells. Thus, our data indicate that kaempferol exerts profound antiosteoclastogenic effects by specifically antagonizing TNF receptor family action on bone cells at two distinct levels, by disrupting production of osteoclastogenic cytokines from osteoblasts and attenuating osteoclast precursor cell differentiation.
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PMID:Differential activity of kaempferol and quercetin in attenuating tumor necrosis factor receptor family signaling in bone cells. 1643 28


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