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)

Total hip arthroplasty (THA) has provided dramatic pain relief and improvement in function for millions of patients with end-stage arthritis; however, periprosthetic osteolysis following THA has become increasingly recognized as a major clinical problem in both cemented and cementless reconstructions. An aggressive granulomatous tissue (interfacial membrane) consisting predominantly of fibroblasts, aggregates of macrophages, and foreign body giant cells develops at the interface of bone/prostheses or bone/cement. It is believed that particulate wear debris from prosthetic materials and/or bone cement are phagocytized by histiocytic cells of interfacial membrane and then these cells produce inflammatory mediators and proteolytic enzymes to provoke a cascade of osteolytic events. In this paper, we studied in vitro responsiveness of various cell types to particulate wear debris. Although titanium and titanium alloys demonstrate excellent biocompatibility in bulk from, titanium in particulate form can provoke a variety of cellular responses. We have found that small-sized Ti particles of phagocytosable size, a commonly encountered particle species in the periprosthetic tissues of failed THAs, stimulate macrophages to secrete various mediators of bone resorption (prostaglandin E(2), interleukin-1, interleukin-6, and tumor necrosis factor-alpha from macrophages and cause bone resorption in organ culture. In addition, we have shown that phagocytosable titanium particles stimulate fibroblasts to up-regulate the expression of matrix metalloproteinases (stromelysin and collagenase) without a substantial effect on the tissue inhibitor of these enzymes (TIMP). Titanium particulates also have a suppressive effect on procollagen synthesis by osteoblast-like cell line. Thus, titanium particulates have the capacity to stimulate bone resorption and inhibit bone matrix formation. In this series of experiments, we have also shown in vitro inhibitory effect of certain pharmaceutical components (indomethacin, misoprostol) upon bone resorption in organ culture, which may indicate a potential therapeutic intervention to prevent or treat particulate-induced pathological bone resorption in total joint arthroplasties.
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PMID:Particulate-Induced, Prostaglandin- and Cytokine-Mediated Bone Resorption in an Experimental System and in Failed Joint Replacements. 1185 95

Metabolism of the extracellular matrix (ECM) is a complex process that becomes disregulated in disease states characterized by chronic inflammation of joints, as is seen in rheumatoid arthritis or fibrosis of the lung. The participation of certain cytokines in this process is generally accepted (transforming growth factor-beta induces fibrosis), while the roles of other cytokines are less clear. Oncostatin M (OSM) is a member of the interleukin-6/leukaemia inhibitory factor (or gp130) cytokine family, and its participation in inflammation and the regulation of ECM metabolism is supported by a number of activities identified in vitro, including regulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1. Local overexpression of transforming growth factor-beta has been shown to be fibrogenic in mouse lung, whereas local OSM overexpression via intra-articular administration has been shown to induce a pannus-like inflammatory response in the synovium of mouse knee joints. Here we examine the effects of OSM in the context of those of transforming growth factor-beta using an established adenovirus vector that expresses mOSM (AdmOSM). We administered the virus intra-nasally into Balb/C mice to achieve high expression of OSM in the lung, and examined the effects at various time points. AdmOSM resulted in a vigorous inflammatory response by day 7 which was characterized by an elevation of neutrophil and mononuclear cell numbers and a marked increase in collagen deposition. These data support the use of such systems to study the ECM in vivo, and indicate a potential role for OSM in inflammatory responses that can modulate steady-state ECM deposition in Balb/C mice.
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PMID:Modulation of extracellular matrix using adenovirus vectors. 1202 35

STAT3, a member of signal transducers and activators of transcription (STATs) originally discovered as mediators in cytokine signaling pathways, plays an active role in oncogenesis. However, the function of STAT3 in signaling multistage carcinogenesis, especially in transformation of tumor-promotion sensitive epithelial cells has not been elucidated. The present study demonstrates that STAT3 is activated in interleukin-6 induced transformation in mouse skin epithelial cells. DNA binding and transcriptional activities of STAT3 were significantly increased by interleukin-6. This induced anchorage-independent transformation in tumor-promotion sensitive JB6 mouse skin P+ cells but not in the resistant variant P- cells. Two forms of dominant negative STAT3 (mutant of transcriptional domain, mF, or DNA-binding domain, mD) were stably transfected into P+ cells. Activation of STAT3 was abolished and importantly, interleukin-6 induced anchorage-independent growth was absent in both mutant STAT3 transfectants. To determine the genes targeted by STAT3, three matrix metalloproteinase proteins linked with carcinogenesis of epithelial cells were analysed. Both basal and interleukin-6 induced expression of collagenase I and stromelysin I, but not gelatinase A, were inhibited in the mutant STAT3 transfectants. Furthermore, transfection of a wild type STAT3 restored STAT3 transactivation and response to interleukin-6 induced transformation in mutant STAT3 transfectants, which up-regulated collagenase I and stromelysin I as well. Together, these results provide the first evidence that STAT3 activation is required in the progression of multistage carcinogenesis of mouse skin epithelial cells, and matrix metalloproteinases are actively involved in STAT3-mediated cell transformation.
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PMID:STAT3 activation is required for interleukin-6 induced transformation in tumor-promotion sensitive mouse skin epithelial cells. 1203 77

To elucidate the pathogenesis of periapical lesion-associated bone resorption, a disease model of Wistar rat molar was employed. After lesion induction, the mRNAs encoding for matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) in the developing lesions were detected by in situ hybridization at day 5, 10, 15 and 20, respectively. At day 5, MMP-1, IL-6 and COX-2 mRNAs appeared predominantly in macrophages. During day 15 to day 20, increased expressions of these mediators were also found in osteoblasts but to a lesser extent compared with those in macrophages. MMP-1 mRNA was also detected in osteoclasts. In contrast, expression of the TIMP-1 gene was noted primarily in osteoblasts and was less pronounced compared with that of MMP-1. The mediator-expressing cells aggregated in the vicinity of bone resorption areas and their numbers increased with time. These data suggest that macrophages and osteoblasts are involved in the development of periapical lesions, and that they promote bone resorption by producing MMP-1, IL-6 and COX-2. In addition, administration of a specific COX-2 inhibitor, meloxicam, reduced the extent of periapical bone resorption by 43% and simultaneously diminished the numbers of cells synthesizing MMP-1 and IL-6 mRNAs. These results further elucidate the significance of COX-2 in disease progression of periapical lesions as it modulates indirectly the production of MMP-1 and IL-6.
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PMID:Sequential expressions of MMP-1, TIMP-1, IL-6, and COX-2 genes in induced periapical lesions in rats. 1212 Jul 11

Expression of the endothelial cell-specific molecule (ESM)-1 was originally identified in lung and kidney endothelial cells, where its expression is regulated by cytokines. In vitro, ESM-1 interferes with the molecular mechanisms of immune cell migration by binding to adhesion molecules. In this study, we have explored the expression of ESM-1 in isolated human adipocytes and in rat adipose tissue depots. Human primary adipocytes were cultivated after collagenase digestion and used for in vitro incubation studies. Adipocytes were also isolated from different fat depots of Sprague-Dawley rats. Gene expression was quantified by TaqMan RT-PCR using specific human and rat ESM-1 primers. The cellular localisation of ESM-1 was determined by confocal microscopy using a specific antibody. ESM-1 expression in human adipocytes was stimulated by phorbol ester, an activator of protein kinase C, and by retinoic acid, an activator of nuclear receptors. The maximum increase in gene expression was 3.2-fold after 72 h treatment with phorbol ester and 4.6-fold after 72 h treatment with retinoic acid. The highest expression was found in subcutaneous rat adipose tissue - two-fold compared to epididymal and six-fold compared to intrascapular brown adipose tissue. As obesity is related to systemic inflammation (examplified by increased circulating levels of C-reactive protein and interleukin-6), the formation of ESM-1 in adipocytes and its activation by protein kinase C may play a role in the regulation of inflammatory processes.
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PMID:Endothelial cell specific molecule-1--a newly identified protein in adipocytes. 1277 64

In this study, we investigated the effect of inflammatory cytokines on matrix metalloproteinase (MMP-1) and TIMP-1 production in human dermal fibroblasts, which play a pivotal role in wound healing, ranging from the synthesis and remodeling of extracellular matrix (ECM) to the synthesis of growth factors. The balance of MMPs and TIMPs is crucial in directing successful wound repair. Human adult dermal fibroblasts were seeded in six well plates (7.5 x 10(4) cells/ml) in complete media. Eighty to ninety percent confluent cells were treated with interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) (10 ng/ml) for 6h in serum free media with suitable controls run in triplicate. Supernatants were assayed for pro-MMP-1 & TIMP-1. Extracted total RNA was used for reverse transcription polymerase chain reaction (RT-PCR) with sequence specific primers for MMP-1, TIMP-1 and beta-actin. Signal intensity was normalized to the internal control (beta-actin). Statistical analysis used ANOVA. MMP-1 and TIMP-1 mRNA expression were markedly increased with IL-6 and TNF-alpha treatment and remains unchanged with IL-1beta. Pro-MMP-1 protein levels are unchanged with TNF-alpha and significantly increased with IL-1beta and IL-6 treatment. However, TNF-alpha significantly increases TIMP-1 protein levels. Data suggests differential regulation of MMP-1 and TIMP-1 protein levels by the cytokines found in stimulated dermal fibroblasts. Further characterization of this response will provide an understanding of the mechanisms of pathogenesis of extracellular matrix (ECM) and the potential role of metalloproteinases in tissue remodeling after injury.
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PMID:Matrix metalloproteinase expression in cytokine stimulated human dermal fibroblasts. 1292 75

Chronic hypoxia is implicated in lung fibrosis, which is characterized by enhanced deposition of extracellular matrix (ECM) molecules. Transforming growth factor-beta (TGF-beta) plays a key role in fibroblast homeostasis and is involved in disease states characterized by excessive fibrosis, such as pulmonary fibrosis. In this study, we investigated if hypoxia modulates the effects of TGF-beta on the expression of gelatinases: matrix metalloproteinase (MMP)-2 and MMP-9, interstitial collagenases: MMP-1 and MMP-13, tissue inhibitors of MMP (TIMP), collagen type I and interleukin-6 (IL-6). Primary human lung fibroblasts, established from tissue biopsies, were cultivated under normoxia or hypoxia in the presence of TGF-beta1, TGF-beta2 or TGF-beta3. Gelatinases were assessed by gelatin zymography and collagenases, TIMP, collagen type I and IL-6 by ELISA. Under normoxia fibroblasts secreted MMP-2, collagenases, TIMP, collagen type I and IL-6. TGF-betas significantly decreased MMP-1 and increased TIMP-1, IL-6 and collagen type I. Hypoxia significantly enhanced MMP-2, and collagenases. Compared to normoxia, the combination of TGF-beta and hypoxia reduced MMP-1, and further amplified the level of TIMP, IL-6, and collagen type I. Thus, in human lung fibroblasts hypoxia significantly increases the TGF-betas-induced secretion of collagen type I and may be associated to the accumulation of ECM observed in lung fibrosis.
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PMID:Hypoxia modulates the effects of transforming growth factor-beta isoforms on matrix-formation by primary human lung fibroblasts. 1456 88

Excessive production of interleukin-6 (IL-6) and metalloproteinases (MMPs) have been implicated in the pathogenesis of rheumatoid arthritis. Lipoxin A4 (LXA4) and transforming growth factor beta 2 (TGF-beta 2), mediators with potential anti-inflammatory activities, were tested to determine how they affect IL-1 beta-dependent release of IL-6 and MMPs in human fibroblast like synoviocytes. The results showed dramatic differences between the mediators: TGF-beta 2 acted synergistically with IL-1 beta to stimulate IL-6 protein levels, whereas LXA4 inhibited IL-6 expression in dose- and time-dependent manner. Inhibition, by LXA4 was abrogated when cells were pre-incubated with antibody against the LXA4R whereas TGF-beta 2 by itself had no significant effect on IL-6 or MMP levels. LXA4, at nanomolar concentrations, altered the MMP-1 and MMP-3 expression levels of IL-1 beta and TGF-beta 2 stimulated fibroblast like synoviocytes at 5 days. Furthermore, IL-1 beta and TGF-beta 2 up-regulated LXA4R mRNA. These results demonstrate, for the first time, that LXA4Rs mediate the effects of LXA4 on inflammatory responses after combined stimulation of human fibroblast like synoviocytes with IL-1 beta and TGF-beta 2. These activities might constitute an important mechanism by which LXA4 regulates human synovial fibroblast activation.
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PMID:Lipoxin A4 counteracts synergistic activation of human fibroblast-like synoviocytes. 1500 Aug 62

The structural rearrangement of collagen fibres in hypertrophic scar causes abnormal contracture, low tensile strength, and raised scars, which cause functional impairment and disfigurement. It is hypothesized that changes in the genes of cytokines, extracellular matrix proteins, and proteins regulating programmed cell death are related to hypertrophic scar formation. To test this hypothesis, fibroblasts were cultured from hypertrophic scars and their response to interleukin-6 (IL-6) stimulation was studied by defining their gene expression profiles. Affymetrix gene chip analysis was used to identify up- or down-regulation in the 12 625 genes present in the affymetrix array. RT-PCR and ELISA assays were used to validate microarray expression profiles further. Comparison of gene profiles showed an increase of 12 genes in hypertrophic scar fibroblasts compared with normal skin fibroblasts, while the expression of 14 genes decreased. Thirty-three genes were affected by IL-6 treatment in the hypertrophic scar fibroblasts, while 57 genes were affected in normal skin fibroblasts. Messenger RNA to beta-actin ratios for matrix metalloproteinase-1 (MMP-1) and MMP-3 were increased with IL-6 in normal skin fibroblasts from 2.43 +/- 0.06 to 5.50 +/- 0.45 and from 0.75 +/- 0.09 to 1.98 +/- 0.01, respectively. No change in these matrix metalloproteinases could be shown with IL-6 stimulation in hypertrophic scar fibroblasts. Secreted protein levels of pro-MMP-1 and MMP-3 were elevated in the supernatants from normal skin fibroblasts from 2.00 +/- 0.09 and 1.72 +/- 0.10 ng/ml to 4.60 +/- 0.12 and 3.41 +/- 0.20 ng/ml, respectively, after treatment with IL-6 (p < 0.05). No changes were observed in hypertrophic scar fibroblasts treated with IL-6. Values are means +/- SEM. The absence of any up-regulation of MMP-1 and MMP-3 in hypertrophic scar fibroblasts, in response to IL-6, suggests that suppression of matrix metalloproteinases may play a role in the excessive accumulation of collagen formed in hypertrophic scars. While the pathogenesis of abnormal hypertrophic scars remains poorly understood, the use of gene expression arrays may prove helpful in identifying the mechanisms responsible for this type of abnormal scar formation and in formulating an effective therapeutic protocol.
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PMID:Gene expression profiles from hypertrophic scar fibroblasts before and after IL-6 stimulation. 1509 75

We performed an observational study on 137 patients undergoing carotid endarterectomy (CEA). Patients on statins were less likely to have had symptoms in the 4 weeks before CEA (p = 0.0049) and were less likely to have spontaneous cerebral embolization detected by transcranial Doppler (p = 0.0459). Carotid plaques retrieved at CEA from patients taking statins revealed significantly lower concentrations of matrix metalloproteinase-1 (p = 0.0176), matrix metalloproteinase-9 (p = 0.0018), and interleukin-6 (p = 0.0005).
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PMID:Comparison of levels of matrix metalloproteinases, tissue inhibitor of metalloproteinases, interleukins, and tissue necrosis factor in carotid endarterectomy specimens from patients on versus not on statins preoperatively. 1521 30

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