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)

Platelet-derived growth factor (PDGF) BB, a mitogen that stimulates bone resorption, increases the expression of interleukin-6 (IL-6), a cytokine that induces osteoclast recruitment. The mechanisms involved in IL-6 induction by PDGF BB are poorly understood. We examined the effect of PDGF BB on IL-6 expression in cultures of osteoblasts from fetal rat calvariae (Ob cells). PDGF BB increased IL-6 mRNA and heterogeneous nuclear RNA levels, the rate of transcription, and the activity of base pairs (bp) -2906 to +20 IL-6 promoter fragments transiently transfected into Ob cells. Deletion analysis revealed two responsive regions, one containing an activator protein-1 (AP-1) site located between bp -276 and -257, and a second, less well defined, downstream of -257. Targeted mutations of a cyclic AMP-responsive element (CRE), and nuclear factor-IL-6 and nuclear factor-kappaB binding sites in a bp -257 to +20 IL-6 construct that was transfected into Ob cells, revealed that the CRE also contributed to IL-6 promoter induction by PDGF BB. Electrophoretic mobility shift assay revealed AP-1 and CRE nuclear protein complexes that were enhanced by PDGF BB. Supershift assays revealed binding of Jun and Fos to AP-1 and CRE sequences and binding of activating transcription factor-2 to CRE. In conclusion, PDGF BB induces IL-6 transcription in osteoblasts by regulating nuclear proteins of the AP-1 complex and activating transcription factor-2.
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PMID:Platelet-derived growth factor induces interleukin-6 transcription in osteoblasts through the activator protein-1 complex and activating transcription factor-2. 1003 79

Partial hepatectomy and toxic liver damage induce signals in the liver that result in rapid changes in the transcriptional milieu, including activation of latent transcription factors NF-kappa B and STAT3, and induction of expression of early growth response genes. Several of these changes within hepatocytes, including STAT3 and NF-kappa B induction are dependent on the cytokines, TNF alpha and interleukin-6 (IL-6), that are presumably released from non-parenchymal liver cells within minutes of the hepatectomy. IL-6 is a critical factor in the mitogenic response during liver regeneration and is important for both cell cycle progression and protection from liver injury. However, it is not a complete factor in that it is responsible for only a subset of the gene expression changes that occur after hepatectomy and is insufficient alone to cause hepatic DNA synthesis. C/EBP beta, a leucine zipper transcription factor, acts in an IL-6 independent fashion to induce a separate set of genes and proteins and is also required for normal liver regeneration. Moreover, some early growth response genes such as PRL-1, which encodes a nuclear protein tyrosine phosphatase, are induced normally in the absence of C/EBP beta and IL-6 and highlight the role of other transcriptional complexes such as Egr-1 in the early phases of liver regeneration. Thus, cytokine-dependent and -independent pathways act cooperatively to control the complex series of events that result in liver regeneration. The requirement for multiple signals also protects the liver from undergoing hyperplasia in the absence of a compensatory need.
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PMID:Transcriptional regulatory signals define cytokine-dependent and -independent pathways in liver regeneration. 1042 95

The liver plays a critical role in the inflammatory response to injury; however, the mechanisms by which the liver is affected and how it influences the rest of the immune system are not well understood. Partial hepatectomy is a direct injury to the liver, whereas a burn is an indirect injury to liver, but both injuries appear to produce damage to the liver. In this study, we used a mouse model of 25% total body surface area and 40% total body surface area full-thickness burns to investigate the mechanism of liver damage and response to burn injury by measuring levels of c-Jun messenger (m)RNA, NFkappaB nuclear protein, interleukin-6, transaminases, and liver tissue histology over time. c-Jun and NFkappaB are 2 transcription factors that are induced by partial hepatectomy and related to hepatocyte injury and growth. In both groups of mice with burns, expression of c-Jun mRNA and NFkappaB nuclear protein was activated within 30 minutes after the burn injury, followed by increased levels of interleukin-6 and, finally, elevated enzyme levels. Liver injuries were similar in both groups despite the magnitude of the burns. We believe that these gene products are initiated in the hepatocyte injury after a burn and that they precede other inflammatory responses such as cytokine release, plasma transaminase levels, and histologic changes.
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PMID:Gene expression and cytokine and enzyme activation in the liver after a burn injury. 1075 46

The nuclear protein Ki-67 is a proliferation index, as it is expressed only by dividing cells. In this study, we investigated the clinical significance of Ki-67 determination on bone marrow biopsies of 35 patients with newly diagnosed multiple myeloma (MM). We examined the correlation of Ki-67 with other MM proliferation-related factors: interleukin-6 (IL-6), IL-10, bone marrow infiltration by plasma cells, serum lactate dehydrogenase (LDH), and beta 2 microglobulin (b2M). Ki-67 expression was also correlated with the survival rate of the patients. The results showed that Ki-67 expression increases with increasing stage of disease according to Durie-Salmon (classification stage III vs. I and II, p < 0.001). Furthermore, infiltration, IL-6, LDH, and b2M increase significantly with advancing stage of disease (p < 0.004). All parameters studied were significantly higher in patients versus controls. Ki-67 correlated with IL-6 (r: 0.422, p < 0.01), LDH (r: 0.437, p < 0.01), and b2M (r: 0.478, p < 0.004). There was a marked difference in survival between patients with MM with Ki-67 greater than 8% and patients with Ki-67 less than 8%, in favor of the latter (p < 0.07). We conclude that Ki-67 determination during routine pathological analysis of bone marrow in newly diagnosed MM could provide useful information about the proliferative activity and prognosis of the disease.
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PMID:Ki-67 proliferation index: correlation with prognostic parameters and outcome in multiple myeloma. 1475 26

This study tests the hypothesis that transcription factor activation by exposure of macrophages to titanium particles can be modulated by the addition of the antiinflammatory cytokine, interleukin 10 (IL-10). The experiments were carried out with primary human monocyte/macrophages that were treated in the presence or absence of IL-10 with and without exposure to titanium particles. The time course for experiments varied from 1 h-5 h for analysis of nuclear protein and up to 48 h for analysis of cytokine release. Transcription factor translocation to the nucleus was analyzed using electrophoretic gel shift assays and cytokine release was quantified by enzyme-linked immunosorbent assay. Addition of titanium particles increased release of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta). In addition, titantium particle induced translocation of the transcription factors, NF-kappa B and NF-IL6, in the nucleus within 1 h. Treatment of macrophages with IL-10 prior to exposure to titanium particles decreased translocation of NF-IL6 but did not significantly alter nuclear levels of NF-kappa B. In addition, pretreatment of the cells with IL-10 decreased particle-induced cytokine release. These data show that antiinflammatory cytokines may provide a mechanism by which particle-induced inflammatory response may be modulated in vivo.
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PMID:Effects of interleukin-10 on titanium particle-induced macrophage transcription factor activation and cytokine expression in vitro. 1499 49

IkappaB-zeta is an inducible nuclear protein that interacts with nuclear factor-kappaB (NF-kappaB) via its carboxyl-terminal ankyrin-repeats. Previous studies using an NF-kappaB reporter have shown that IkappaB-zeta inhibits the activity of NF-kappaB. In the present study, we dissected the amino-terminal region of IkappaB-zeta, which shows no homology to any other proteins. Indirect immunofluorescence studies demonstrated the presence of a bipartite nuclear localization signal spanning amino acids 163-178. Using GAL4 fusion proteins, we found that internal fragments containing amino acids 329-402 possessed intrinsic transcriptional activation activity. Interestingly, the activity was not detected in GAL4 fusion proteins of the full-length IkappaB-zeta. On the other hand, the GAL4-dependent transcriptional activity was generated by co-expression of the GAL4-NF-kappaB p50 subunit fusion protein and the full-length IkappaB-zeta, neither of which exhibited the activity on their own. A new splicing variant, IkappaB-zeta(D), with a deletion of amino acids 236-429, was found to lack transactivation activity. Forced expression of IkappaB-zeta, but not IkappaB-zeta(D), augmented interleukin-6 production, indicating the functional significance of the transactivation activity. In contrast, tumor necrosis factor-alpha production was inhibited by expression of IkappaB-zeta, highlighting the dual functions of this molecule. These results indicate that IkappaB-zeta harbors latent transcriptional activation activity, and that the activity is expressed upon interaction with the NF-kappaB p50 subunit. In addition to the inhibitory activity on NF-kappaB-mediated transcription, the transcriptional activation activity of IkappaB-zeta should be crucial for the regulation of inflammation.
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PMID:Positive and negative regulation of nuclear factor-kappaB-mediated transcription by IkappaB-zeta, an inducible nuclear protein. 1561 16

Multiple sclerosis is an inflammatory, neurodegenerative disease for which experimental autoimmune encephalomyelitis (EAE) is a model. Treatments with estrogens have been shown to decrease the severity of EAE through anti-inflammatory mechanisms. Here we investigated whether treatment with an estrogen receptor alpha (ERalpha) ligand could recapitulate the estrogen-mediated protection in clinical EAE. We then went on to examine both anti-inflammatory and neuroprotective mechanisms. EAE was induced in wild-type, ERalpha-, or ERbeta-deficient mice, and each was treated with the highly selective ERalpha agonist, propyl pyrazole triol, to determine the effect on clinical outcomes, as well as on inflammatory and neurodegenerative changes. ERalpha ligand treatment ameliorated clinical disease in both wild-type and ERbeta knock-out mice, but not in ERalpha knock-out mice, thereby demonstrating that the ERalpha ligand maintained ERalpha selectivity in vivo during disease. ERalpha ligand treatment also induced favorable changes in autoantigen-specific cytokine production in the peripheral immune system [decreased TNFalpha, interferon-gamma, and interleukin-6, with increased interleukin-5] and decreased CNS white matter inflammation and demyelination. Interestingly, decreased neuronal staining [NeuN+ (neuronal-specific nuclear protein)/beta3-tubulin+/Nissl], accompanied by increased immunolabeling of microglial/monocyte (Mac 3+) cells surrounding these abnormal neurons, was observed in gray matter of spinal cords of EAE mice at the earliest stage of clinical disease, 1-2 d after the onset of clinical signs. Treatment with either estradiol or the ERalpha ligand significantly reduced this gray matter pathology. In conclusion, treatment with an ERalpha ligand is highly selective in vivo, mediating both anti-inflammatory and neuroprotective effects in EAE.
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PMID:Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis. 1679 89

Previous results indicate that enhanced glucose transporter (GLUT)1 expression mediates the deleterious effects of metabolic and hemodynamic perturbations leading to diabetic kidney disease. First screening for altered gene expression in GLUT1 overexpressing cells (GT1) by Affymetrix microarray analysis revealed upregulation of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) expression, which was verified by RT-PCR. Subsequently, IL-6 and VEGF protein production was more than 3-fold increased in the GT1 cells. This upregulation was independent from each other. Studies on the underlying transcriptional mechanisms by gelshift assays and siRNA approach implicated activation of AP-1 in the increased expression of both, IL-6 and VEGF. We found also increased nuclear protein levels of hypoxia-inducible factor (HIF)-1alpha and enhanced DNA binding activity to a hypoxia responsible element located in the VEGF promoter. Knock-down of HIF-1alpha reduced the VEGF expression to 50% with an additive effect of AP-1 gene silencing down to 24%. The IL-6 expression was not affected by reducing HIF-1alpha. In conclusion our results link increased GLUT1 levels leading to excess glucose metabolism under normoglycemic conditions and altered gene expression of pathogenetic factors involved in diabetic kidney disease.
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PMID:Increased glucose uptake and metabolism in mesangial cells overexpressing glucose transporter 1 increases interleukin-6 and vascular endothelial growth factor production: role of AP-1 and HIF-1alpha. 1716 25

Osteopontin (OPN) is expressed in many tissues during inflammatory responses. After spinal cord injury, microglia expresses OPN at the site of injury during the early to subacute stages. However, the function of OPN in spinal cord injury is not well understood. This study examines the responses of OPN knock-out (KO) and wild-type (WT) mice to spinal cord contusion injury. KO and WT mice were injured with a modified New York University impactor. Weights of 10 or 5.6 g were dropped 6.25 mm onto the T13 spinal cord under isoflurane anesthesia. At 24 h, homogenized spinal cords were analyzed for total potassium concentration to estimate lesion volumes. Expression of apoptotic genes, proinflammatory cytokines, and nerve growth factors was measured by reverse transcription (RT)-PCR and Western blot. In a series of animals, locomotor recovery was assessed with the Basso mouse scale (BMS) for 6 weeks, and histological analyses was performed to determine tissue preservation. Lesion volume showed no significant differences between KO and WT mice at 24 h. RT-PCR indicated that KO mice had significantly less Bcl-2, tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 mRNA compared with WT controls. Western blot also showed that KO had significantly less Bcl-2 7 d after spinal cord injury. KO mice had significantly worse BMS locomotor scores than WT at 6 weeks. KO mice also had a significantly reduced area of spared white matter and fewer neuronal-specific nuclear protein-positive neurons in the spinal cord surrounding the impact site. This result supports a potential neuroprotective role for OPN in the inflammatory response to spinal cord injury.
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PMID:Osteopontin-deficient mice exhibit less inflammation, greater tissue damage, and impaired locomotor recovery from spinal cord injury compared with wild-type controls. 1739 76

During inflammation, drug metabolism and clearance are altered due to suppression of hepatic drug-metabolizing enzyme (DME) genes and their regulatory nuclear receptors (NRs) [pregnane X receptor, constitutive androstane receptor, and retinoid X receptor alpha (RXRalpha)]. The bacterial endotoxin, lipopolysaccharide (LPS), induces expression of proinflammatory cytokines in the liver, which contribute to altered DME expression. LPS binds to the cell-surface receptor, Toll-like receptor 4 (TLR4), which initiates a signal transduction cascade, including recruitment of the Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP). However, the role of TLR4 and TIRAP in LPS-mediated regulation of hepatic DME gene expression is not known. Wild-type (C3HeB/FeJ), TLR4-mutant (C3H/HeJ), TIRAP(+/+), and TIRAP(-/-) mice were injected i.p. with LPs. RNA levels of the major hepatic DME, Cyp3a11 and Ugt1a1, and the NRs were suppressed approximately 60 to 70% by LPS in wild-type but not in the TLR4-mutant mice. The nuclear protein levels of RXRalpha were reduced by LPS in wild-type but not in TLR4-mutant mice. Induction of hepatic cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6), c-Jun N-terminal kinase, and nuclear factor-kappaB was blocked in TLR4-mutant mice. Surprisingly, LPS had the same effect on cytokines, kinases, NRs, and DME genes in livers of both TIRAP(+/+) and TIRAP(-/-) mice, indicating that TIRAP is not essential for TLR4-mediated suppression of NRs and DMEs in liver. However, TIRAP(-/-) mice have reduced serum cytokine expression compared with TIRAP(+/+) mice in response to LPS. This shows that although TIRAP mediates inflammatory responses induced by LPS, it is not essential in regulating LPS-mediated alterations of gene expression in liver.
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PMID:Regulation of hepatic drug-metabolizing enzyme genes by Toll-like receptor 4 signaling is independent of Toll-interleukin 1 receptor domain-containing adaptor protein. 1793 22

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