Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Freshly isolated leukemic cells from patients with adult T-cell leukemia (ATL) and human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of interleukin-6 (IL-6) protein and mRNA. To clarify the mechanisms that lead to the activation of IL-6 gene in HTLV-I-infected cells, we first studied the regulatory regions in the IL-6 gene transcription by transfection of chloramphenicol acetyltransferase (CAT) reporter plasmids containing the IL-6 promoter. When transfected into HTLV-I-infected T-cell lines MT-2 and HUT-102, IL-6 promoter/CAT plasmids were strongly activated without any stimulation. By deletion analysis of 5' upstream region of IL-6 promoter, the DNA region between -73 and -59 bp from the transcription start site of IL-6 gene was important in the expression of IL-6/CAT activities in HTLV-I-infected cells. This region contains nuclear factor (NF)-kappa B binding site. The site-directed mutation of the kappa B motif in IL-6/CAT plasmid resulted in the complete abrogation of IL-6 promoter activity in these cells. Furthermore, when IL-6 promoter/CAT plasmid was introduced into an HTLV-I-uninfected T-cell line, Jurkat, IL-6 promoter activity was silent in the basal level, but strongly increased by the cotransfection with an HTLV-I tax expression plasmid. However, tax expression plasmid showed no transactivation activity, when kappa B site was mutated in IL-6 promoter/CAT plasmid. We found that the IL-6 kappa B site specifically formed a complex with NF-kappa B-containing nuclear extracts from MT-2 and HUT-102 cells. Finally, transfection of HTLV-I tax into Jurkat cells resulted in induction of specific binding of nuclear extracts to the NF-kappa B sequence. These results strongly suggest that HTLV-I tax gene may transactivate IL-6 gene through kappa B site in HTLV-I-positive T-cell lines and activation of NF-kappa B may be crucial in HTLV-I-induced IL-6 gene activation in ATL.
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PMID:Transcriptional regulation of the human interleukin-6 gene promoter in human T-cell leukemia virus type I-infected T-cell lines: evidence for the involvement of NF-kappa B. 794 64

To detect transcripts encoding the interleukin-6 receptor (IL-6R) molecule lacking the transmembrane (TM) domain, in various cell lines and peripheral blood mononuclear cells (PBMC), we used the polymerase chain reaction (PCR) with primer pairs that flank the TM domain and which were selected to generate a 398-bp fragment. We detected 398-bp and 304-bp DNA molecules in the PCR products of the U1, J22HL60, MT-2, MT-4, U937 and HL60 cell lines and of PBMC isolated from several individuals. The sequencing analysis of both DNA molecules showed that a 94-bp region consisting of the TM domain of IL-6R was deleted in the 304-bp molecule. Moreover, we detected a soluble (s) IL-6R protein of 45 kDa in culture supernatants of the MT-2, MT-4 and U937 cell lines by radioimmunoprecipitation using specific antibodies against sIL-6R. Our results indicate that active deletion of the TM domain by alternative splicing of mRNA represents one mechanism for release of sIL-6R into the culture supernatants of cells, or into serum or urine.
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PMID:Soluble interleukin-6 receptors released from T cell or granulocyte/macrophage cell lines and human peripheral blood mononuclear cells are generated through an alternative splicing mechanism. 805 53

Leukemia inhibitory factor (LIF), similar to interleukin-6 (IL-6), is a glycoprotein growth factor and differentiation regulator that has pleiotropic activity in several cellular systems. Recent reports of constitutive IL-6 production from spontaneously proliferating cells from human T-cell leukemia virus (HTLV)-infected individuals led us to examine the expression of IL-6 and LIF during HTLV infection. In vitro infection of peripheral blood lymphocytes with HTLV-I was associated with production of both soluble LIF and IL-6 in conjunction with the increasing HTLV antigen concentration. Northern blot analysis of T-cell lines generated from individuals infected with HTLV-I (MT-2, HuT-102, FS, EG, SP) and HTLV-II (Mo-T, H2A, H2E) demonstrated a marked increase in constitutive expression of LIF and IL-6 transcripts, as compared with uninfected cell lines (HuT-78, Jurkat). The constitutive expression of LIF and IL-6 was independent of presence of IL-2 in the culture medium, as both IL-2-independent (MT-2, HuT-102, SP, Mo-T) and IL-2-dependent (FS, EG, H2A, H2E) cell lines expressed LIF and IL-6 transcripts. Furthermore, LIF and IL-6 RNA expression in an HTLV-I-infected cell line (MT-2) was enhanced by phorbol ester stimulation via mechanisms that appear to be dependent on the posttranscriptional regulatory controls. These results show that both LIF and IL-6 are produced by HTLV-I- and HTLV-II-infected cells, which could potentially alter the transcriptional regulation of HTLV gene expression by inducing certain early response genes.
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PMID:Infection with human T-lymphotropic viruses leads to constitutive expression of leukemia inhibitory factor and interleukin-6. 809 6

The comparative influence of dietary zinc status and recombinant human interleukin-1 alpha (rhIL-1 alpha) and recombinant human interleukin-6 (rhIL-6) on metallothionein (MT) gene expression was examined in rat bone marrow and liver. Growing male rats were fed a diet with 5 (restricted), 30 (control), or 180 (supplemented) mg Zn/kg for 14 d. On d 15, rats were injected with 5 micrograms of rhIL-1 alpha or rhIL-6. Marrow metallothionein responded directly to dietary zinc but did not respond to these cytokines. Significantly less zinc accumulated in marrow from the zinc-restricted rats compared with control or supplemented rats. Analysis of metallothionein isoform mRNA expression showed MT-1 is the primary gene expressed in marrow. A significant interaction between dietary zinc and cytokine treatment was observed in the liver. Hepatic metallothionein induction following both rhIL-1 alpha and rhIL-6 injection was directly related to dietary zinc intake. Expression of hepatic metallothionein isoform mRNAs suggested MT-1 responded to zinc and MT-2 responded to cytokines. These results indicate that metallothionein gene expression in both the marrow and the liver responds to dietary zinc status. In contrast, liver metallothionein expression can be altered by these cytokines, which are known to act on many cell types. Furthermore, these results suggest that bone marrow metallothionein could be of importance in the development of marrow cells.
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PMID:Metallothionein expression in rat bone marrow is dependent on dietary zinc but not dependent on interleukin-1 or interleukin-6. 846 65

Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human autoimmune disease multiple sclerosis (MS). Proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are considered important for induction and pathogenesis of EAE/MS disease, which is characterized by significant inflammation and neuroglial damage. We have recently shown that the exogenous administration of the antioxidant protein zinc-metallothionein-II (Zn-MT-II) significantly decreased the clinical symptoms, mortality, and leukocyte infiltration of the CNS during EAE. However, it is not known how EAE progression is regulated nor how cytokine production and cell death can be reduced. We herewith demonstrate that treatment with Zn-MT-II significantly decreased the CNS expression of IL-6 and TNF-alpha during EAE. Zn-MT-II treatment could also significantly reduce apoptotic cell death of neurons and oligodendrocytes during EAE, as judged by using TUNEL and immunoreactivity for cytochrome c and caspases 1 and 3. In contrast, the number of apoptotic lymphocytes and macrophages was less affected by Zn-MT-II treatment. The Zn-MT-II-induced decrease in proinflammatory cytokines and apoptosis during EAE could contribute to the reported diminution of clinical symptoms and mortality in EAE-immunized rats receiving Zn-MT-II treatment. Our results demonstrate that MT-II reduces the CNS expression of proinflammatory cytokines and the number of apoptotic neurons during EAE in vivo and that MT-II might be a potentially useful factor for treatment of EAE/MS.
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PMID:Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE). 1142 79

Synthesis of metallothionein (MT) is induced by interferon-alpha (IFN-alpha) in vitro and in vivo. In addition, IFN-alpha promotes redistribution of zinc (Zn) from the plasma to the liver in mice. However, it is not clear if IFN-alpha induces hepatic MT synthesis directly or indirectly via liberation of other cytokines. In order to address this issue, we determined hepatic MT levels, Zn concentration in plasma, liver, and urine, and plasma levels interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha) in rats following intramuscular injection of human IFN-alpha (1.5 x 10(6) UI/m(2)). Animals were housed in metabolic cages and sacrificed at various times after IFN-alpha administration. Zn concentrations in serum, urine, and hepatic tissue were determined by atomic absorption spectrophotometry. MT protein was measured using the MT silver saturation method and expression of MT-1 and MT-2 mRNA was measured by RT-PCR. Plasma levels of rat IL-1, IL-6, and TNFalpha were determined using an ELISA method. Hepatic MT levels began to increase at 2 h following IFN-alpha administration and reached maximum levels at 12 h post-treatment. Induction of MT gene expression was confirmed by increases in MT-1 and MT-2 mRNA levels 6, 12, and 18 h after IFN-alpha administration. IFN-alpha treatment also resulted in biphasic increases in hepatic Zn, with levels peaking at 2 h, the time-point when MT levels are first increased, and again at 18 h. Concurrently, there were decreases in serum Zn levels at these time points, suggesting IFN-alpha induced movement of Zn from the blood to hepatic tissue. The decrease in serum Zn was not due to increased excretion since urinary Zn levels were unaffected following IFN-alpha treatment. IFN-alpha administration had no effect on plasma IL-1, IL-6, and TNFalpha levels. These results show that IFN-alpha promotes the increase of hepatic MT levels and plasma/liver redistribution directly, without IL-1, IL-6, or TNFalpha participation.
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PMID:Interferon alpha induction of metallothionein in rat liver is not linked to interleukin-1, interleukin-6, or tumor necrosis factor alpha. 1600 9

Metallothioneins are low molecular weight, cysteine-rich, metal-binding proteins, which can be induced by heavy metal ions, cytokines, stress, and hormones. To investigate the roles of the main cis-acting elements involved in the inducible expression of metallothionein gene in fish, the 5'-upstream region of crucian carp (Carassius cuvieri) metallothionein-I gene had been cloned and analyzed after our previous work on metallothionein-II. In its upstream region, several putative cis-acting elements, including nine metal regulatory elements (MREs), one antioxidant response element, one E-box, and three interleukin-6 responsive elements, etc. were found. The nine metal regulatory elements are confined in less than 1000 bp from ATG start codon and organized into two clusters with different roles to the induction of the metallothionein-I expression. Deletion mutant assays demonstrated that both the distal and proximal clusters of metal regulatory elements contributed to the basal expression of the metallothionein-I, but only the proximal cluster was the chief contributor to the metal fold induction. In transient luciferase reporter assays, Zn2+ and Cd2+ served as much stronger inducers than Cu2+ to the metallothionein-I expression. H2O2 also could activate the metallothionein-I promoter about two-fold, which was mediated by the antioxidant response element (TGACAACGC, -437/-445). In conclusion, our studies demonstrate the roles of metal regulatory element and antioxidant response element in the induction of crucian carp metallothionein-I gene, and provide the regulatory mechanism for the use of fish metallothionein as a biomarker for monitoring of metal contamination in waters.
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PMID:Cloning and functional characterization of 5'-upstream region of metallothionein-I gene from crucian carp (Carassius cuvieri). 1733 34

Oncostatin M (OSM) is a member of the interleukin-6 (IL-6) cytokine family and known to be induced in the nervous system as a result of cell stress. OSM is expressed in most human brain tumors, but the effects on tumor cells are unclear. The cytokine is known to activate the JAK/STAT signaling pathway by binding to its receptors gp130/OSMbeta or gp130/LIFRbeta and thereby initiating activation or suppression of a number of STAT target genes. The objective of the study was to identify OSM-regulated genes that could help in understanding the function of OSM in glioma cells. The glioma cell line, U1242MG was stimulated by OSM and the gene expression patterns were analyzed by microarray. In total, nineteen differentially expressed genes were selected due to high intensity, level of up/down-regulation and biological functions. The differentially expressed genes were verified using quantitative PCR. Additional validation of the confirmed OSM-induced proteins was performed in human astrocytoma tissues by immunohistochemistry. Among the up-regulated genes were CHI3L1, PLAU, MT2A and EPAS1. These genes are known to be involved in cell matrix remodeling, migration, proliferation control and angiogenesis. The results suggest that OSM induces genes that might contribute to the development and progression of astrocytomas.
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PMID:Oncostatin M-induced genes in human astrocytomas. 1798 72

Metallothionein (MT) as a potent antioxidant can affect energy metabolism. The present study was undertaken to investigate the association between MT gene polymorphism and type 2 diabetes mellitus. Using the PCR-based restriction fragment length polymorphism method, seven single nucleotide polymorphisms (SNPs) in MT genes (rs8052394 and rs11076161 in MT1A gene, rs8052334, rs964372, and rs7191779 in MT1B gene, rs708274 in MT1E gene, and rs10636 in MT2A gene) were detected in 851 Chinese people of Han descent (397 diabetes and 454 controls). Several serum measurements were also examined randomly for 43 diabetic patients and 41 controls. The frequency distributions of the G allele in SNP rs8052394 of MT1A gene were significantly associated with the incidence of type 2 diabetes. There was no difference between patients and controls for the rest of six SNPs. Serum levels of interleukin-6 and tumor necrosis factor-alpha were higher, and serum superoxide dismutase activity was significantly lower in the diabetic group than those in the control group. For diabetic patients, serum superoxide dismutase activity was significantly lower in GG or GA carriers than those of AA carriers of rs8052394 SNP. Increased serum levels in diabetic patients were positively associated with rs964372 SNP, and type 2 diabetes with neuropathy was positively associated with rs10636 and rs11076161. These results suggest that multiple SNPs in MT genes are associated with diabetes and its clinical symptoms. Furthermore, MT1A gene in rs8052394 SNP is most likely the predisposition gene locus for diabetes or changes of serum superoxide dismutase activity.
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PMID:Polymorphisms in metallothionein-1 and -2 genes associated with the risk of type 2 diabetes mellitus and its complications. 1834 10

Infection with human T-cell leukemia virus type 1 (HTLV-1) leads sometimes to the development of adult T-cell lymphoma/leukemia (ATL), which is invariably fatal and often associated with humoral hypercalcemia of malignancy. The transformation of infected CD4 T cells and the pathogenesis of leukemia have been studied with great limitation in tissue culture and patients. To better understand the pathogenesis and perform preclinical drug studies, animal models of ATL are urgently needed. In mice, inoculation of HTLV-1 cell lines mostly leads to development of localized lymphomas. To develop an ATL animal model with leukemic spread of ATL cells, mouse strains with different well-defined immune deficiencies were inoculated intraperitoneally with different HTLV-1-infected cell lines (ACH.2, C8166, MT-2, MET-1). Inoculation of MET-1 cells into NOD/SCID mice provided the best model system for slowly developing T-cell leukemia with multiple organ involvement. In leukemic mice, an increase in serum calcium levels correlated with expression of receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand on leukemic cells and secretion of parathyroid hormone-related protein and interleukin-6. In contrast to the other cell lines that did not spread systemically, MET-1 expressed both the adhesion molecules CD11a (LFA-1alpha) and CD49d (VLA-4alpha) and produced or induced expression of matrix metalloproteinases 1, 2, 3, and 9, thus underlining the importance of these molecules in the spread of adult T-cell leukemia cells. The MET-1/NOD/SCID model will be useful for developing interventions against invasion and spread of leukemic cells and subsequent humoral hypercalcemia of malignancy.
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PMID:Expression of tumor invasion factors determines systemic engraftment and induction of humoral hypercalcemia in a mouse model of adult T-cell leukemia. 1942 77


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