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)

High levels of ambient air pollution are associated with exacerbation of asthma and respiratory morbidity, yet little is known concerning the mechanisms of inflammation and toxicity by components of inhaled particulate matter (PM). Brief inhalation of PM(2.5) (particles of an aerodynamic diameter of < 2.5 microns) (300 microg/m(3) air for 6 h followed by a period of 24 h in clean air) by either C3H/HeJ or C57/BL6 mice caused significant (P </= 0.05) increases in steady-state messenger RNA (mRNA) levels of a number of nuclear factor (NF)-kappaB-associated and/ or -regulated genes, including tumor necrosis factor-alpha and -beta, interleukin-6, interferon-gamma, and transforming growth factor-beta. Lung mRNA levels of lymphotoxin-beta and macrophage migration inhibitory factor were unchanged. In murine C10 alveolar cells and an NF-kappaB-luciferase reporter cell line, exposure to PM(2.5) at noncytotoxic concentrations resulted in increases in transcriptional activation of NF-kappaB-dependent gene expression which were inhibited in the presence of catalase. Early and persistent increases in intracellular oxidants, as measured by flow cytometry and cell imaging using the oxidant probe 2'-7'-dichlorofluoroscin diacetate, were observed in epithelial cells exposed to PM(2.5) and ultrafine carbon black particles. Studies here are the first to show NF-kappaB-related inflammatory and cytokine gene expression after inhalation of PM(2.5) and oxidant-dependent induction of NF-kappaB activity by PM(2.5) in pulmonary epithelial cells.
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PMID:Inhaled particulate matter causes expression of nuclear factor (NF)-kappaB-related genes and oxidant-dependent NF-kappaB activation in vitro. 1091 84

Vascular endothelial cell activation and dysfunction are critical early events in atherosclerosis. Selected dietary lipids (eg, fatty acids) may be atherogenic by activating endothelial cells and by potentiating an inflammatory response. Due to their prooxidant property, unsaturated fatty acids may play a critical role in endothelial cell activation and injury. To test this hypothesis, porcine endothelial cells were exposed to 18-carbon fatty acids differing in the degree of unsaturation, ie, 90 micromol/L stearic (18:0), oleic (18:1n-9), linoleic (18:2n-6), or linolenic acid (18:3n-3) for 6 to 24 hours and/or tumor necrosis factor alpha ([TNF-alpha] 500 U/L) for up to 3 hours. Compared with control cultures, treatment with 18:0 and 18:2 decreased glutathione levels, suggesting an increase in cellular oxidative stress. Both 18:2 and 18:0 activated the transcription factor nuclear factor kappaB (NF-kappaB) the most and 18:1 the least. This NF-kappaB-dependent transcription was confirmed in endothelial cells by luciferase reporter gene assay. The fatty acid-mediated activation of NF-kappaB was blocked by preenrichment of the cultures with 25 micromol/L vitamin E. All fatty acids except 18:1 and 18:3 increased transendothelial albumin transfer, and 18:2 caused the most marked disruption of endothelial integrity. Preenrichment of endothelial cells with 18:2 followed by exposure to TNF-alpha resulted in a 100% increase in interleukin-6 (IL-6) production compared with TNF-alpha exposure alone. In contrast, cellular preenrichment with 18:0, 18:1, or 18:3 had no effect on TNF-alpha-mediated production of IL-6. Cellular release of radiolabeled arachidonic acid (20:4) was markedly increased only by cell exposure to 18:2 and 18:3, and the release of 20:4 appeared to be mainly from the phosphatidylethanolamine fraction. These data suggest that oleic acid does not activate endothelial cells. Furthermore, linoleic acid and other omega-6 fatty acids appear to be the most proinflammatory and possibly atherogenic fatty acids.
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PMID:Fatty acid-mediated activation of vascular endothelial cells. 1095 18

Cathelicidins are a family of antimicrobial peptides prominent in the host defense mechanisms of several mammalian species. In addition to their antimicrobial activities, these peptides have been implicated in wound healing, angiogenesis, and other innate immune mechanisms. To investigate the regulatory mechanisms of cathelicidin gene expression, we conducted in vitro experiments evaluating the bone marrow cell expression of two porcine cathelicidins, PR-39 and protegrin, and cloned and evaluated the promoter sequence of PR-39. In addition, we evaluated in vivo kinetics of cathelicidin gene expression in pigs during an infection with Salmonella enterica serovar Typhimurium. Lipopolysaccharide (LPS) increased PR-39 and protegrin mRNA expression, which was ameliorated by polymyxin B. Concentrations of PR-39 in supernatants from bone marrow cell cultures were increased 10-fold after LPS stimulation. Similarly, interleukin-6 (IL-6) and all-trans retinoic acid (RA) markedly induced cathelicidin gene expression. To verify the transcriptional activation of the PR-39 gene by these agents, we made a PR-39 promoter-luciferase construct containing the full-length PR-39 promoter driving luciferase gene expression and transiently transfected PK-15 epithelial cells. RA and IL-6 increased luciferase activity in PK-15 cells transfected with the PR-39 promoter-luciferase reporter. Similarly, Salmonella-challenged pigs showed increased expression of PR-39 and protegrin mRNA in bone marrow cells at 6 and 24 h postchallenge. Taken together, these findings show that bacterial products (LPS), IL-6, RA, and Salmonella infection enhance the expression of the cathelicidins, PR-39 and protegrin, in bone marrow progenitor cells, and we suggest that extrinsic modulation of this innate host defense mechanism may be possible.
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PMID:Regulation of cathelicidin gene expression: induction by lipopolysaccharide, interleukin-6, retinoic acid, and Salmonella enterica serovar typhimurium infection. 1099 53

Interleukin-6 (IL-6)-type cytokines stimulate osteoclast formation by activating the glycoprotein 130 (gp130) receptor subunit on stromal/osteoblastic cells, which in turn leads to signal transducer and activator of transcription 3 (STAT3)-mediated expression of receptor activator of NF-kappaB ligand (RANKL). Based on evidence that gp130 expression is regulated by a variety of cytokines and hormones, we have determined here whether changes in gp130 levels directly contribute to the magnitude of the osteoclastogenic stimulus delivered by IL-6-type cytokines. To accomplish this, gp130 protein levels were modulated using a tetracycline-regulated expression system in a stromal/osteoblastic cell line, UAMS-32, which supports osteoclast formation. Removal of doxycycline from the culture medium elevated gp130 expression and increased the responsiveness of a STAT-responsive promoter-luciferase construct to IL-6 complexed with its soluble receptor (IL-6+sIL-6R), but diminished the responsiveness to oncostatin M (OSM). IL-6+sIL-6R-stimulated osteoclast formation was greater when osteoclast precursors were cocultured with the cells expressing elevated gp130 levels than when cells expressing low gp130 levels were used. However, increased gp130 levels reduced OSM-stimulated osteoclast formation. These results establish that the level of gp130 in stromal/osteoblastic cells directly modulates the magnitude of the osteoclastogenic response to IL-6-type cytokines such that an increase in gp130 increases the cellular responsiveness to IL-6+sIL-6R but reduces responsiveness to OSM.
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PMID:Expression levels of gp130 in bone marrow stromal cells determine the magnitude of osteoclastogenic signals generated by IL-6-type cytokines. 1099 44

The mucin-like glycoprotein episialin (MUC1) is highly overproduced by a number of human carcinomas. We have shown previously in a variety of mammalian cell lines that overexpression of this very large transmembrane molecule diminishes cellular adhesion, suggesting that episialin/MUC1 overexpression may play an important role in tumor invasion and metastasis. By using in situ hybridization, we show here that episialin/MUC1 mRNA expression can be increased more than 10-fold in breast carcinoma cells relative to the expression in adjacent normal breast epithelium. In search of the molecular mechanism of this overexpression, we observed that the episialin/MUC1 promoter contains a candidate binding site for transcription factors of the STAT family approximately 500 base pairs upstream of the transcription start site. Cytokines and/or growth factors such as interleukin-6 or interferon-gamma can activate STATs. In the human breast carcinoma cell line T47D, both compounds are able to stimulate transcription of a luciferase reporter gene under the control of a 750-base pair MUC1 promoter fragment proximal to the transcription start site. The observed increase is entirely mediated by the single STAT-binding site, since mutation of this site abolishes stimulation of the reporter by interleukin-6 and interferon-gamma. In addition, mutation of the STAT site also decreased the promoter activity in nonstimulated T47D cells, suggesting that the STAT-binding site is among the elements that are involved in the overexpression of MUC1 in tumor cells.
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PMID:A stat-responsive element in the promoter of the episialin/MUC1 gene is involved in its overexpression in carcinoma cells. 1108 45

Flavonoids are naturally occurring polyphenolic compounds with a wide distribution throughout the plant kingdom. In the present study, we compared the ability of several flavonoids to modulate the production of proinflammatory molecules from lipopolysaccharide (LPS)-stimulated macrophages and investigated their mechanism(s) of action. Pretreatment of RAW 264.7 with luteolin, luteolin-7-glucoside, quercetin, and the isoflavonoid genistein inhibited both the LPS-stimulated TNF-alpha and interleukin-6 release, whereas eriodictyol and hesperetin only inhibited TNF-alpha release. From the compounds tested luteolin and quercetin were the most potent in inhibiting cytokine production with an IC(50) of less than 1 and 5 microM for TNF-alpha release, respectively. To determine the mechanisms by which flavonoids inhibit LPS signaling, we used luteolin and determined its ability to interfere with total protein tyrosine phosphorylation as well as Akt phosphorylation and nuclear factor-kappaB activation. Pretreatment of the cells with luteolin attenuated LPS-induced tyrosine phosphorylation of many discrete proteins. Moreover, luteolin inhibited LPS-induced phosphorylation of Akt. Treatment of macrophages with LPS resulted in increased IkappaB-alpha phosphorylation and reduced the levels of IkappaB-alpha. Pretreatment of cells with luteolin abolished the effects of LPS on IkappaB-alpha. To determine the functional relevance of the phosphorylation events observed with IkappaB-alpha, macrophages were transfected either with a control vector or a vector coding for the luciferase reporter gene under the control of kappaB cis-acting elements. Incubation of transfected RAW 264.7 cells with LPS increased luciferase activity in a luteolin-sensitive manner. We conclude that luteolin inhibits protein tyrosine phosphorylation, nuclear factor-kappaB-mediated gene expression and proinflammatory cytokine production in murine macrophages.
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PMID:Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages. 1112 79

Estrogens are important mediators of bone homeostasis, and postmenopausal estrogen replacement therapy is extensively used to prevent osteoporosis. The biological effects of estrogen are mediated by receptors belonging to the superfamily of steroid/thyroid nuclear receptors, estrogen receptor (ER)alpha and ER beta. ER alpha, not only trans-activates target genes in a hormone-specific fashion, but it can also neutralize other transcriptional activators, such as nuclear factor (NF)-kappa B, causing repression of their target genes. A major mechanism by which estrogens prevent osteoporosis seems to be repression of transcription of NF-kappa B target genes, such as the osteoclast-activating cytokines interleukin-6 and interleukin-1. To study the capacity of both ERs in repression of NF-kappa B signaling in bone cells, we first carried out transient transfections with ER alpha or ER beta of the human osteoblastic U2-OS cell line, in which endogenous NF-kappa B was stimulated by tumor necrosis factor alpha. Repression by ER alpha was already observed without 17 beta-estradiol, whereas addition of the ligand increased repression to 90%. ER beta, however, was able to repress NF-kappa B activity only in the presence of ligand. Because it is known that some antiestrogens can also display tissue-specific agonistic properties, 4-hydroxytamoxifen was tested for its capacity in repressing NF-kappa B activity and was found to be active (albeit less efficient than 17 beta-estradiol) and, interestingly, only with ER alpha. The pure antagonist ICI 164,384 was incapable of repressing through any ER subtypes. Deletion analysis and the use of receptor ER alpha/ER beta-chimeras showed that the A/B domain, containing activation function-1, is essential for this suppressive action. Next, we developed stable transfectants of the human osteoblastic U2-OS cell line containing ER alpha or ER beta in combination with an NF-kappa B luciferase reporter construct. In these cell lines, repression of NF-kappa B activity was only mediated through ER alpha and not through ER beta. These findings offer new insights into the specific role of both ER subtypes in bone homeostasis and could eventually help in developing more specific medical intervention strategies for osteoporosis.
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PMID:4-hydroxytamoxifen trans-represses nuclear factor-kappa B activity in human osteoblastic U2-OS cells through estrogen receptor (ER)alpha, and not through ER beta. 1118 31

The circulating level of angiotensinogen (AGT) is dynamically regulated as an important determinant of blood pressure and electrolyte homeostasis. Because the mechanisms controlling the regulated expression of human angiotensinogen (hAGT) are unknown, we investigated the inducible regulation of the hAGT gene in well differentiated HepG2 cells. Interleukin-6 (IL-6) stimulation produced a 3.2-fold increase in hAGT mRNA peaking at 96 h after stimulation. Deletional mutagenesis of the hAGT promoter in transient transfection assays identified an IL-6 response domain between nucleotides -350 and -122 containing three reiterated motifs, termed human acute phase response elements (hAPREs). Although mutation of each site individually caused a fall in IL-6-inducible luciferase activity, mutation of all three sites was required to block the IL-6 effect. Electrophoretic mobility shift assay (EMSA), supershift, and microaffinity DNA binding assays indicate IL-6-inducible high-affinity binding of signal transducers and activators of transcription 1 and -3 (STAT1 and -3) to hAPRE1 and -3 but only low-affinity binding to hAPRE2. Expression of a dominant-negative form of STAT3, but not STAT1, produced a concentration-dependent reduction in IL-6-induced hAGT transcription and endogenous mRNA expression. These data indicate that STAT3 plays a major role in hAGT gene induction through three functionally distinct hAPREs in its promoter and suggest a mechanism for its up-regulation during the acute-phase response.
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PMID:Role of signal transducers and activators of transcription 1 and -3 in inducible regulation of the human angiotensinogen gene by interleukin-6. 1122 45

It has been well established that overexpression of Cyclooxygenase-2 (Cox-2) in epithelial cells inhibits apoptosis and increases the invasiveness of malignant cells, favoring tumorigenesis and metastasis. However, the molecular mechanism that regulates Cox-2 expression has not been well defined in gastric carcinoma. In this study, we examined whether the Cox-2 expression could be regulated by hyper-methylation of the Cox-2 CpG island (spanning from -590 to +186 with respect to the transcription initiation site) in human gastric carcinoma cell lines. By Southern analysis, we found that three gastric cells (SNU-601, -620, and -719) without Cox-2 expression demonstrated hyper-methylation at the Cox-2 CpG island. A detailed methylation pattern using bisulfite sequencing analysis revealed that all of the CpG sites were completely methylated in SNU-601. Treatment with demethylating agents effectively reactivated the expression of Cox-2 and restored IL-1beta sensitivity in the previously resistant SNU-601. By transient transfection experiments, we demonstrate that constitutively active Cox-2 promoter activities were exhibited even without an exogenous stimulation in SNU-601. Furthermore, when the motif of the nuclear factor for interleukin-6 expression site, the cyclic AMP response element, or both was subjected to point mutation, the constitutive luciferase activity was markedly reduced. In addition, Cox-2 promoter activity was completely blocked by in vitro methylation of all of the CpG sites in the Cox-2 promoter region with SssI (CpG) methylase in SNU-601. Taken together, these results indicate that transcriptional repression of Cox-2 is caused by hyper-methylation of the Cox-2 CpG island in gastric carcinoma cell lines.
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PMID:Transcriptional silencing of Cyclooxygenase-2 by hyper-methylation of the 5' CpG island in human gastric carcinoma cells. 1138

To investigate the level at which protein kinase C (PKC) regulates expression of interleukin-6 (IL-6) in osteoblastic cells, effects of several PKC antagonists and PKC down-regulation by phorbol ester were studied in UMR-106 osteoblastic cells that had been transiently transfected with a -224/+11-base pair (bp) IL-6 promoter coupled to a luciferase reporter. Parathyroid hormone (PTH) elicited a dose-dependent stimulation of the IL-6 promoter expression, with significant increases produced by 5 h of treatment with concentrations of PTH as low as 10(-14) M. The increase in IL-6 promoter expression was inhibited by the PKC antagonists GF109203X, 30 nM to 1 microM, and calphostin C, 250 nM. Prior down-regulation of PKC with 100 nM phorbol-12,13-dibutyrate (PDBU) for 48 h inhibited the PTH effect as well as the smaller stimulatory effects elicited by tumor necrosis factor alpha (TNF-alpha), 10(-9)-10(-8) M, and by IL-1beta, 1-10 ng/ml. In contrast to these findings, the stimulatory effects of PTH, TNF-alpha, and IL-1beta on the IL-6 promoter expression were enhanced by staurosporine. Treatment with GF109203X or down-regulation of PKC with PDBU prevented the stimulatory effects of staurosporine. PKC activity was increased by staurosporine. The findings with staurosporine are consistent with our earlier observations that this agent enhances the calcium signaling and bone resorption elicited by PTH. The studies support the role of PKC in the stimulatory effects of PTH, TNF-alpha, and IL-1beta on IL-6 expression.
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PMID:Stimulation of interleukin-6 promoter by parathyroid hormone, tumor necrosis factor alpha, and interleukin-1beta in UMR-106 osteoblastic cells is inhibited by protein kinase C antagonists. 1145 Jun 97

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