UNIPROT:P05231 - FACTA Search

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)

Magnesium (Mg) inhibits the influx of calcium in vascular smooth muscle cells. The purposes of this study were to test the hypothesis that an intravenous administration of magnesium might effect the complement response and to determine the effects of a magnesium pretreatment of patients with acute myocardial infarction (AMI) on the incidence of reperfusion injuries. Thirty-eight AMI patients were treated with coronary reperfusion therapy within 6 hours of onset. They were randomly divided into two groups: group pretreated with intravenous magnesium sulfate (0.27 mmol/kg) (magnesium group, n = 19), and nonpretreated controls (placebo group). The reperfusion injuries observed within 1 hour after the coronary reperfusion included arrhythmias, aggravated chest pain, and ST segment elevation in 12-lead electrocardiograms. Coronary recanalization was performed in 36 patients. The incidence of reperfusion arrhythmia was significantly lower in the magnesium group than in the placebo group (17% vs 78%, p<0.001). At the postreperfusion stage, there was a tendency for the degree of ST segment reelevation in the magnesium group lower than in the placebo group (2.5 +/- 2.3 mm vs 4.7 +/- 3.8 mm, p = 0.07). No marked difference was observed in the incidence of chest pain aggravation between the two groups (67% vs 73%, ns). The peak serum levels of interleukin-6 (IL-6) were significantly lower in the magnesium group than those in the placebo group (38.9 +/- 25.0 vs 92.3 +/- 76.5 pg/mL, p = 0.016). The peak serum levels of matrix metalloproteinase-1 (MMP-1) were lower than those in the placebo group (16.2 +/- 4.8 vs 19.7 +/- 9.0 ng/mL, p = 0.09), but the difference was not significant. A positive correlation was observed between the peak MMP-1 values and the peak IL-6 values (r = 0.57, p = 0.001) in all patients. Increased serum ionized Mg2+ may inhibit arrhythmic recurrence and the production of IL-6 and MMP-1 after reperfusion and prevent the increase of myocardial lesions caused by calcium overload on myocytes. The increased IL-6 production may induce MMP-1, leading to tissue organ injury. Pretreatment with magnesium sulfate may protect the myocardium of AMI patients from reperfusion injuries.
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PMID:Effect of magnesium sulfate pretreatment and significance of matrix metalloproteinase-1 and interleukin-6 levels in coronary reperfusion therapy for patients with acute myocardial infarction. 1043 97

Bisphosphonates have recently been introduced in the therapeutic armamentarium for the long-term treatment of patients with multiple myeloma (MM). These pyrophosphate analogs not only reduce the occurrence of skeletal-related events but also provide patients with a clinical benefit and improve the survival of some of them. We investigated the effects of two bisphosphonates, pamidronate and zoledronate, on both myeloma cells and bone marrow stromal cells (BMSCs). We show here that both bisphosphonates induce both myeloma cell and BMSC apoptosis. Furthermore, at lower concentrations, they induce a significant inhibition (40% and 60%, respectively) of the constitutive production of interleukin-6 (IL-6) by BMSCs. We have recently shown that BMSCs produce MMP-1, the major metalloproteinase involved in the initiation of bone resorption, production up-regulated by IL-1beta. Here, we demonstrate that zoledronate significantly inhibits MMP-1 production by BMSCs stimulated with IL-1beta more efficiently than pamidronate. However, zoledronate and to a lesser extent pamidronate are responsible for an up-regulation of MMP-2 secretion by BMSCs. MMP-2 is involved both in bone resorption and in the metastatic process. In conclusion, the apoptosis of myeloma cells and BMSCs and the inhibition of both IL-6 and MMP-1 production induced by bisphosphonates, mainly zoledronate, could have antitumoral effects in patients with MM. However, the up-regulation of MMP-2 secretion observed in vitro suggests a putative risk of tumor cell dissemination in vivo when using these new potent bisphosphonates. This potentially deleterious effect could be abolished by combining bisphosphonates with metalloproteinase inhibitors.
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PMID:Zoledronate is a potent inhibitor of myeloma cell growth and secretion of IL-6 and MMP-1 by the tumoral environment. 1062 64

Although parathyroid hormone (PTH) has the ability to stimulate bone growth in both rats and humans, its mechanism of action is not fully understood at the molecular level. An in vitro marker that reflects the in vivo anabolic actions of PTH would facilitate the discovery of small-molecule compounds that stimulate bone growth. We therefore compared the patterns of gene expression in three cell lines treated with PTH. The levels of c-fos, collagenase, interleukin-6 (IL-6), and collagen mRNA were determined by reverse transcription-polymerase chain reaction (RT-PCR) in three osteoblast-like cell lines. The most responsive marker was c-fos, which was induced 5-10-fold after 1 h of PTH treatment in the UMR106-01 cell line. Because it is a critical early response gene in bone growth, we investigated the possibility of using c-fos stimulation as a method to screen for compounds that can stimulate bone formation. A highly sensitive, medium-throughput RT-PCR assay for c-fos mRNA expression was established using the Taqmantrade mark Detection System (Perkin Elmer, Mississauga, Ontario). Cells were treated with a series of compounds to determine the specificity of c-fos stimulation. Of the compounds tested, only PTH, prostaglandin E(2), 8-bromo-cAMP, and forskolin induced c-fos mRNA levels, indicating that this assay was specific for compounds that are known to induce cAMP and stimulate bone growth. These results indicate that a simple in vitro assay for c-fos may be a reliable method for the screening of compounds that stimulate bone growth in vivo.
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PMID:Development of an In Vitro Screening Assay for Compounds that Increase Bone Formation. 1083 33

Oncostatin M (OSM) is a multifunctional cytokine, a member of the interleukin-6/leukemia inhibitory factor (IL-6/LIF) family, that can regulate a number of connective-tissue cell types in vitro including cartilage and synovial tissue-derived fibroblasts, however its role in joint inflammation in vivo is not clear. We have analyzed murine OSM (muOSM) activity in vitro and in vivo in mouse joint tissue, to determine the potential role of this cytokine in local joint inflammation and pathology. The effects of muOSM and other IL-6/LIF cytokines on mouse synovial fibroblast cultures were assessed in vitro and showed induction of monocyte chemotactic protein-1, interleukin-6, and tissue inhibitor metalloproteinase-1, as well as enhancement of colony growth in soft agarose culture. Other IL-6/LIF cytokines including IL-6, LIF, or cardiotrophin-1, did not have such effects when tested at relatively high concentrations (20 ng/ml). To assess effects of muOSM in articular joints in vivo, we used recombinant adenovirus expressing muOSM cDNA (AdmuOSM) and injected purified recombinant virus (10(6) to 10(8) pfu) intra-articularly into the knees of various mouse strains. Histological analysis revealed dramatic alterations in the synovium but not in synovium of knees treated with the control virus Ad-dl70 or knees treated with Adm-IL-6 encoding biologically active murine IL-6. AdmuOSM effects were characterized by increases in the synovial cell proliferation, infiltration of mononuclear cells, and increases in extracellular matrix deposition that were evident at day 4, but much more marked at days 7, 14, and 21 after administration. The synovium took on characteristics similar to pannus and appeared to contact and invade cartilage. Collectively, these results provide good evidence that OSM regulates synovial fibroblast function differently than other IL-6-type cytokines, and can induce a proliferative invasive phenotype of synovium in vivo in mice on overexpression. We suggest that OSM may contribute to pathology in arthritis.
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PMID:Murine oncostatin M stimulates mouse synovial fibroblasts in vitro and induces inflammation and destruction in mouse joints in vivo. 1102 23

Cell-cell contact of myeloma-derived cell lines (MDCL) or fresh myeloma cells with bone marrow stromal cells (BMSC) is known to induce interleukin-6 (IL-6) and matrix metalloproteinase-1 (MMP-1) production by a marrow stromal cell line. To determine if other BMSC transcripts are altered during cell-cell contact between BMSC and tumor cells, we have used cell lines ARH77 and U266 in an in vitro model. Using mRNA differential display and reverse transcriptase-polymerase chain reaction (RT-PCR), it was determined that a total of 141 transcripts were either upregulated or downregulated in the BMSC on contact with cell membrane from cell lines ARH77 and U266. Induction of two of these transcripts, interleukin-6 (IL-6) and gp130 in the BMSC by ARH77 cell membranes was studied in greater detail. Real-time PCR was used to quantitate transcript levels of gp130, IL-6, and 36b4, a housekeeping gene. Cycloheximide (CHX) alone increased both gp130 and IL-6 transcripts in the BMSC. In addition, CHX caused a superinduction of these transcripts in BMSC exposed to ARH77 cell membranes. The induction of gp130 was independent of the increase in IL-6 mRNA. Upregulation of gp130, a component of the membrane receptors for the IL-6 superfamily, can have profound effects on the response of BMSC to the IL-6 superfamily of cytokines.
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PMID:Acute activation of gp130 gene expression in bone marrow stromal cells by contact with myeloma-derived lymphoblastic cell line ARH77 cell membranes. 1133 Oct 38

Matrix metalloproteinases (MMPs) collectively degrade extracellular matrix and basement membrane proteins in chronic inflammation and bone-destructive lesions. This study examined the ability of immunoglobulin-producing plasma cells, typically present in sites of chronic inflammation, to express collagenases (MMP-8 and -13) in vivo and in vitro. Phorbol-12-myristate-13-acetate, interleukin-6, and tumour necrosis factor-alpha and heparin with the tumour promoter or cytokines potently enhanced (up to nine-fold) MMP-8 and -13 expression by the RPMI 8226 myeloma cell line, as evidenced by western blotting and semi-quantitative reverse transcriptase-polymerase chain reaction. Immunohistochemical analysis and in situ hybridization revealed that plasma cells expressed MMP-8 and -13 focally in periapical granulomas, odontogenic cysts, and malignant plasmacytomas. MMP-8 and MMP-13 from plasma cells can participate in bone organic matrix destruction at sites of chronic inflammation and neoplastic growth. Since MMP-13 was more frequently expressed than MMP-8 in plasma cells of strongly recurring keratocysts and malignant plasmacytomas, it is concluded that plasma cell MMP-13 has a particularly important role in benign and malignant bone-destructive lesions.
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PMID:Expression and induction of collagenases (MMP-8 and -13) in plasma cells associated with bone-destructive lesions. 1140 Jan 51

The question 'Why hepatocellular carcinoma cells are unlikely to metastasize although they have a high proliferative activity?' is a major point of interest from a cancer physiopathological viewpoint. Recent articles about the roles and relationships of some cytokines with matrix degrading enzymes and their inhibitors in various types of normal tissues and malignancies give rise to another question: 'Does tissue inhibitor of metalloproteinase-1 prevent the extrahepatic metastasis of hepatocellular carcinoma cells?' On the basis of many evidences, it is highly probable that under the effect of a possible inducing mechanism of the cytokines interleukin-6, -1 beta and transforming growth factor beta, the increase in concentration of tissue inhibitor of metalloproteinase-1 in hepatocellular carcinoma cause increased type I collagen accumulation and consequent prevention of cellular detachment, which explains why highly proliferative malignant hepatocytes have less metastatic ability.
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PMID:Why hepatocellular carcinoma cells are unlikely to metastasize: is there a role for tissue inhibitor of metalloproteinase-1? 1146 Nov 77

In our RT-PCR screen for cytokine expression in human brain tumors we discovered increased levels of oncostatin M (OSM), ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), all belonging to the interleukin-6 (IL-6) cytokine family, in most of the tumors. The expression of these cytokines in normal adult brain tissue was found to be very low or below detection limit. OSM expression was elevated in most of the tumors and immunohistochemistry analysis showed that the tumor cells contained OSM in their cytoplasm, suggesting they produce this factor. Overexpression of OSM has not previously been reported in primary human brain tumors. The IL-6 cytokine family acts through a common gp130 receptor subunit that activates the JAK/STAT signaling pathway and therefore they have been suggested to have overlapping effects. Tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase 1 (MMP-1) and MMP-3 and IL-6 have been reported to be regulated by OSM. IL-6 was low or absent in the tumors. TIMP-1, MMP-1 and MMP-3 was expressed in most tumors but with no strict correlation to OSM levels.
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PMID:Expression of the IL-6 family cytokines in human brain tumors. 1149 26

Cytokines and proteases are secreted by fibroblasts in response to particulate wear debris, and these proteins are felt to play an important role in the development of osteolysis and implant loosening. Although metallic and polyethlyene debris have been studied extensively, little is known about the cellular responses to hydroxyapatite, despite the wide clinical use of these materials. Therefore, the effects of hydroxyapatite (HA) and hydroxyapatite/beta-tricalciumphosphate (HA/TCP) on cellular proliferation, cytokine gene expression and protein secretion, protease synthesis, and gelatinolytic activity were investigated in human fibroblasts. HA and HA/TCP particles were synthesized, and their effects were compared to the responses elicited by titanium and cobalt chromium. Sample characterization by scanning electron microscopy and Coulter Counter demonstrated that the materials had a mean particle size of less than 10 microm, and all of the particles were compared using the same concentration ranges. Aliquots of particle suspensions were added to human fibroblasts maintained in tissue culture, and dose-response and time-course experiments were performed. Effects of the particles on fibroblast proliferation were assessed, and alterations in cytokine levels were determined by specific enzyme linked immunosorbent assays (ELISA). Cytokines that were evaluated included interleukin-1 (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), all of which have been demonstrated to enhance bone resorption and are associated with osteolysis and implant loosening. Gene expression was determined using Northern blot analysis with cytokine-specific probes, while secretion of the proteases collagenase and stromelysin was determined by Western blot analysis. Functional gelatinolytic assay was assessed using zymogram gels. The particles were evaluated in a concentration range from 0.000021 to 0.021 vol%. All of the particles produced increases in cellular proliferation up to 0.0021 vol%, with the largest increases being seen at 0.021 vol% with HA/TCP and titanium. At the highest concentration, both cobalt chromium and HA samples decreased cellular proliferation relative to lower doses, possibly representing cytotoxicity. Hydroxyapatite particles yielded a 30-fold increase in interleukin-6 secretion compared to unstimulated controls, which was also greater than three times the levels produced by cobalt chromium, titanium, or HA/TCP. HA particles also tripled the secretion of IL-1beta at 0.00021 vol%, and doubled TNF-alpha secretion at 0.021 vol%. Addition of conditioned media prepared by incubation of the particles in culture medium in the absence of cells did not alter the secretion of any of the cytokines. Northern blot analysis using IL-6 probes also demonstrated strong increases with HA compared to the other materials, suggesting that the action of the HA particles was at the level of transcription. Secretion of the protease collagenase was increased by all of the samples including HA when compared to unstimulated controls. Stromelysin secretion into the culture medium was decreased by cobalt chromium, but increased by titanium, HA, and HA/TCP. All of the particles including HA increased the gelatinolytic activity of the fibroblasts. These findings demonstrate that HA and HA/TCP particles are capable of stimulating the expression and secretion of cytokines and proteases that enhance bone resorption, and suggest that particulate debris from implants using these coatings may also increase osteolysis and loosening.
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PMID:Effects of hydroxyapatite particulate debris on the production of cytokines and proteases in human fibroblasts. 1151 71

BMS-275291 is an p.o. bioavailable, sulfhydryl-based matrix metalloproteinase (MMP) inhibitor currently in clinical development for the treatment of cancer. This inhibitor was designed to potently inhibit MMP activities while minimally affecting those of other metalloproteases (e.g., sheddases) involved in the release of cell-associated molecules such as tumor necrosis factor-alpha, tumor necrosis factor-alpha receptor, interleukin-6 receptor, or L-selectin. In vitro, BMS-275291 is a potent inhibitor (nM) of the activities of MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14. BMS-275291 inhibits tumor growth in a B16BL6 model of experimental metastasis, and in this model, BMS-275291 treatment results in a dose-dependent reduction in the number of lung metastases compared with vehicle controls. BMS-275291 also inhibits angiogenesis in a murine angiogenesis model, where once daily treatment with BMS-275291 results in a dose-dependent inhibition of endothelial cell migration into s.c. implanted Matrigel plugs. Pharmacokinetic studies demonstrated that the plasma concentrations of parent BMS-275291 in mice exceeds the in vitro IC(50) values for MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14 for at least 4 h after the administration of a therapeutic dose of BMS-275291. Taken together, these data demonstrate that BMS-275291 inhibits MMP activities that contribute to tumor metastasis and angiogenesis.
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PMID:Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. 1173 31

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