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)

Transcription factor E2F binds to cellular promoters of certain growth- and cell cycle-controlling genes and forms distinct heteromeric complexes with other nuclear proteins. We show here that alpha and beta interferons (alpha, beta) and interleukin-6 abolished the E2F-containing DNA-binding complexes in Daudi Burkitt lymphoma cells and in M1 myeloblastic cells, which responded to the cytokines by suppression of c-myc transcription. Time kinetics studies showed that the abolishment of E2F complexes coincided with reduction of c-myc expression and that both molecular events preceded the cell cycle block in G0/G1 phase. In contrast, the pattern of E2F complexes remained unchanged in an interferon-treated growth-resistant Daudi cell mutant that displayed relaxed regulation of c-myc. All of the DNA-binding E2F complexes, including those containing the retinoblastoma protein (pRB), cyclin A-p33cdk2, and the free forms of E2F, were reduced by interferons or interleukin-6. Their abolishment was unperturbed by pharmacological treatments that alleviated the cyclin A and pRB responses to interferon. Thus, changes in cyclin A expression and pRB phosphorylation are not primary events that influence the pattern of E2F responses to cytokines. Addition of EDTA to cell extracts of interferon-treated Daudi cells restored the DNA-binding activity of E2F, resulting in the appearance of a single E2F complex that exclusively contained pRB. It is suggested that the regulation of E2F by growth-inhibitory cytokines that induce cell cycle exit takes place at the level of the DNA-binding activity, and by that mean it differs basically from the phase-specific regulation of E2F in cycling cells.
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PMID:Interferons and interleukin-6 suppress the DNA-binding activity of E2F in growth-sensitive hematopoietic cells. 768 48

One of the most challenging issues of anti-inflammatory gene therapy is the complexity of inflammatory pathways. Transcription factor NF-kappa B plays a pivotal role in activation of multiple inflammatory molecules, and therefore represents the logical target for intervention. We evaluated the feasibility of suppressing the inflammatory responses in different cell lines through specific inhibition of NF-kappa B by gene transfer of I kappa B alpha, the naturally occurring intracellular inhibitor of NF-kappa B. The I kappa B alpha overexpressing cells were established using retroviral gene transfer or stable transfection with the wild-type (wt) I kappa B alpha cDNA. In all cell types, overexpression of wt I kappa B alpha resulted in a profound (> 100-fold) increase of the I kappa B alpha message and a moderate (two- to three-fold) increase of the I kappa B alpha protein. The effects of the I kappa B alpha overexpression on the NF-kappa B activation and the inflammatory responses varied significantly in different cell lines. In conditionally immortalized human endometrial stromal cells, overexpression of I kappa B alpha prevented both interleukin-1 (IL-1)-inducible degradation of endogenous I kappa B alpha protein and activation of NF-kappa B. Accordingly, induction of cytokines interleukin-8 (IL-8) and Gro gamma was markedly suppressed. In monocytic THP-1 cells, both lipopolysaccharide (LPS)-inducible degradation of I kappa B alpha and NF-kappa B activation were only partially inhibited by overexpression of exogenous I kappa B alpha cDNA. None the less, the LPS-induced transcription of IL-1 beta and secretion of cytokines interleukin-6 (IL-6) and IL-8 were virtually abolished. In epithelial HT-29 cells, no inflammatory responses were inhibited. These results demonstrate the range of responses in various cell lines to gene transfer of I kappa B alpha and indicate the feasibility of suppression of inflammatory responses in appropriate target cells and their progeny by suppression of NF-kappa B.
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PMID:NF-kappa B as a target for anti-inflammatory gene therapy: suppression of inflammatory responses in monocytic and stromal cells by stable gene transfer of I kappa B alpha cDNA. 933 14

Although interleukin-6 (IL-6) alone does not induce the expression of IFN stimulated genes (ISG), a low dose priming of cells with IL-6 strongly enhances the cellular responses to interferon-alpha (IFN-alpha). This effect of IL-6 is not due to superstimulation of the JAK-STAT pathway. Rather, IL-6 induces expression of ISGF3 gamma (p48), a subunit of the multimeric transcription factor ISGF3. As a result IFN-alpha robustly activates gene transcription in IL-6 primed cells. We have shown earlier that the transcription of ISGF3 gamma gene is regulated through a novel element GATE (gamma-IFN activated transcriptional element). We show here IL-6 induces the ISGF3 gamma gene through GATE. Transcription factor C/EBP-beta is required for inducing ISGF3 gamma gene expression through GATE. A mutant C/EBP-beta inhibits the IL-6 inducible ISGF3 gamma gene expression through GATE. Together, these results establish a molecular basis for the synergy between IFNs and IL-6.
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PMID:Interleukin-6 modulates interferon-regulated gene expression by inducing the ISGF3 gamma gene using CCAAT/enhancer binding protein-beta(C/EBP-beta). 1100 86

Transcription factor nuclear factor-kappaB (NF-kappaB) is activated in cerulein pancreatitis and mediates cytokine expression. The role of transcription factor activation in other models of pancreatitis has not been established. Here we report upregulation of NF-kappaB and inflammatory molecules, and their correlation with local pancreatic injury, in a model of severe pancreatitis. Rats received intraductal infusion of taurocholate or saline, and the pancreatic head and tail were analyzed separately. NF-kappaB and activator protein-1 (AP-1) activation were assessed by gel shift assay, and mRNA expression of interleukin-6, tumor necrosis factor-alpha, KC, monocyte chemoattractant protein-1, and inducible nitric oxide synthase was assessed by semiquantitative RT-PCR. Morphological damage and trypsin activation were much greater in the pancreatic head than tail, in parallel with a stronger activation of NF-kappaB and cytokine mRNA. Saline infusion mildly affected these parameters. AP-1 was strongly activated in both pancreatic segments after either taurocholate or saline infusion. NF-kappaB inhibition with N-acetylcysteine ameliorated the local inflammatory response. Correlation between localized NF-kappaB activation, cytokine upregulation, and tissue damage suggests a key role for NF-kappaB in the development of the inflammatory response of acute pancreatitis.
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PMID:Localized pancreatic NF-kappaB activation and inflammatory response in taurocholate-induced pancreatitis. 1135 13

Transcription factor nuclear factor kappaB (NF-kappaB) controls gene expression of a number of genes, including cytokines such as interleukin-6 (IL-6), granulocyte-macrophage (GM)-CSF, and interleukin-8 (IL-8). IL-6 is known to play important roles in the growth of prostate cancer cells, activation of androgen receptor, and prostate-specific protein expression. NF-kappaB is activated by extracellular signals such as proinflammatory cytokines, chemotherapeutic reagents, and radiation. Here we demonstrate that cisplatin (CDDP) and etoposide (VP-16) induce nuclear translocation of NF-kappaB in prostate cancer cell lines, followed by secretion of IL-6. We also demonstrated that the growth of hormone-independent prostate cancer cell lines can be inhibited by the anti-NF-kappaB reagent N-acetyl-L-cysteine (NAC). These observations indicate that NF-kappaB can be a target of new adjuvant therapy against hormone refractory prostate cancer.
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PMID:N-acetyl-L-cysteine enhances chemotherapeutic effect on prostate cancer cells. 1194 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

Neural stem cells (NSC) are capable of differentiating toward neuronal, astrocytic, oligodendrocytic and glial lineages, depending on their spatial location within the central nervous system (CNS). Although, a lot of knowledge has been gained in the understanding of differentiation-specific signaling in hematopoietic (HSC) and mesenchymal (MSC) counterparts, the molecular mechanisms underlying lineage commitment in NSCs are just beginning to be understood. Furthermore, it is not well comprehended as to how the specification of one cell lineage can result in the suppression of parallel pathways in the NSCs. Thus, a thorough understanding of various signal transduction cascades activated via cytokines and growth factors, and the confounding effects of different CNS microenvironments are critically required to determine the full potential of NSCs. Our knowledge on the clonogenic ability, differentiation potential, and the inherent plasticity in both HSCs and MSCs may facilitate the understanding of lineage commitment in the NSCs as well. The information available from the marrow-derived stem cells may be extrapolated toward the similar signaling pathways in the neural precursors. From a number of previous studies, it is apparent that four distinctly different subsets of ligand-receptor superfamilies are involved in determining the fate of NSCs. These include 1) the transforming growth factor type-beta-1 (TGF-beta1) and bone morphogenetic protein (BMP) superfamily; 2) the platelet-derived and epidermal (PDGF/EGF) growth factors; 3) the interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor (IL-6/LIF/CNTF) superfamily; and 4) the EGF-like Notch/Delta group of extracellular ligands. Ligand binding to the cell surface receptor activates the receptor's cytosolic catalytic domain and/or the receptor-associated protein-kinases, which in turn activate intracellular second messengers and different sets of transcription factors. Transcription factor oligomerization, nuclear localization, followed by their recognition of DNA elements, leads to the expression of lineage-specific genes. Association between different groups of transcription factors can also regulate their ability to transcriptionally activate different genes. The limited availability of coactivators and cosuppressors, which can sequester the transcription factor complexes toward or away from a specific gene locus, further adds to the complexity in the cross talk between different signaling cascades. Both concerted actions of temporally regulated signals and convergent effects of different signaling cascades can thus ultimately precipitate the phenotypic changes. It is beginning to be realized that in addition to the cytokines and growth factors, cell-to-cell and cell-to-extracellular matrix (ECM) interactions, are also important within the molecular scenario linked to both proliferation and differentiation of the stem cells. The cell surface molecules, which include cell adhesion molecules (CAMs), integrins, selectins, and the immunoglobulins, are well known to regulate HSC and MSC commitment within different tissue microenvironments and may have direct implications in understanding the NSC cell fate determination within different regions of the brain.
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PMID:Signal transduction pathways involved in the lineage-differentiation of NSCs: can the knowledge gained from blood be used in the brain? 1564 90

Autocrine pathways of proliferative and anti-apoptotic growth factors represent a serious impediment to the treatment of many types of tumors. In particular, interleukin-6 (IL-6), a pleiotropic cytokine known to play a critical role in the survival and growth of multiple myeloma cells, participates in an autocrine stimulation loop that serves to inhibit the induction of apoptosis during chemotherapy. Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme encoded by the SOD2 gene that attenuates oxidative free radicals in the mitochondria by catalyzing the formation of hydrogen peroxide from superoxide radicals. Transcription factor activity and binding is influenced by the oxidative state of cells, and dysregulation of MnSOD levels can result in abnormal patterns of gene expression. In the human multiple myeloma cell line IM-9, an autocrine IL-6 loop exists, which enables the cell to resist the effects of dexamethasone, a common treatment for multiple myeloma. Here, we show that SOD2 expression is epigenetically silenced in IM-9 cells, and replacement of MnSOD reduces cell proliferation and partially restores susceptibility to dexamethasone. The restoration of MnSOD also serves to decrease the expression levels of IL-6 by reducing the ability of activator protein-1, an important mediator of IL-6 expression in multiple myeloma cells, to bind to its enhancer site. These results show the importance of free radical-mediated dysregulation of autocrine growth factor loops in tumor cells and their effect on cell growth and response to chemotherapy.
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PMID:Enforced expression of superoxide dismutase 2/manganese superoxide dismutase disrupts autocrine interleukin-6 stimulation in human multiple myeloma cells and enhances dexamethasone-induced apoptosis. 1602 27

Regulatory T (Treg) cells are essential for self-tolerance and immune homeostasis. Transcription factor Foxp3, a positive regulator of Treg cell differentiation, has been studied to some extent. Signal transducer and activator of transcription factor 3 (STAT3) is known to negatively regulate Foxp3. It is not clear how STAT3 is regulated during Treg differentiation. We show that SMAR1, a known transcription factor and tumor suppressor, is directly involved in maintaining Treg cell fate decision. T-cell-specific conditional knockdown of SMAR1 exhibits increased susceptibility towards inflammatory disorders, such as colitis. The suppressive function of Treg cells is compromised in the absence of SMAR1 leading to increased T helper type 17 (Th17) differentiation and inflammation. Compared with wild-type, the SMAR1(-/-) Treg cells showed increased susceptibility of inflammatory bowel disease in Rag1(-/ -) mice, indicating the role of SMAR1 in compromising Treg cell differentiation resulting in severe colitis. We show that SMAR1 negatively regulate STAT3 expression favoring Foxp3 expression and Treg cell differentiation. SMAR1 binds to the MAR element of STAT3 promoter, present adjacent to interleukin-6 response elements. Thus Foxp3, a major driver of Treg cell differentiation, is regulated by SMAR1 via STAT3 and a fine-tune balance between Treg and Th17 phenotype is maintained.
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PMID:Nuclear matrix protein SMAR1 control regulatory T-cell fate during inflammatory bowel disease (IBD). 2622 Jan 64

The proinflammatory cytokine, interleukin-6 (IL-6), plays a critical role in many chronic inflammatory diseases, particularly inflammatory bowel disease. To investigate the regulation of IL-6 gene expression at the molecular level, genomic DNA sequencing of Jinghai yellow chickens (Gallus gallus) was performed to detect single-nucleotide polymorphisms (SNPs) in the region -2200 base pairs (bp) upstream to 500 bp downstream of IL-6. Transcription factor binding sites and CpG islands in the IL-6 promoter region were predicted using bioinformatics software. Twenty-eight SNP sites were identified in IL-6. Four of these 28 SNPs, three [-357 (G > A), -447 (C > G), and -663 (A > G)] in the 5' regulatory region and one in the 3' non-coding region [3177 (C > T)] are not labelled in GenBank. Bioinformatics analysis revealed 11 SNPs within the promoter region that altered putative transcription factor binding sites. Furthermore, the C-939G mutation in the promoter region may change the number of CpG islands, and SNPs in the 5' regulatory region may influence IL-6 gene expression by altering transcription factor binding or CpG methylation status. Genetic diversity analysis revealed that the newly discovered A-663G site significantly deviated from Hardy-Weinberg equilibrium. These results provide a basis for further exploration of the promoter function of the IL-6 gene and the relationships of these SNPs to intestinal inflammation resistance in chickens.
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PMID:Bioinformatics Analysis of SNPs in IL-6 Gene Promoter of Jinghai Yellow Chickens. 3020 Jun 58


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