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)

Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g. MMP-9). Serine proteases have not yet been investigated in human pituitary adenomas. In this study, paraffin-embedded material from 84 human pituitary adenomas (acromegaly n=18, Cushing's disease n=21, prolactinoma n=18, thyroid-stimulating hormone-secreting adenoma n=1, nonsecreting adenoma n=26) and 9 nontumourous anterior pituitary lobes (obtained from patients with prostate cancer) was immunohistochemically analysed for expression of MMP-2, MMP-9, tissue inhibitor of metalloproteinases-2 (TIMP-2), urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and interleukin-6 (IL-6). Cavernous sinus invasion was determined by assessment of preoperative magnetic resonance imaging and intraoperative inspection (invasive n=50, noninvasive n=34). In pituitary adenomas, reactions were positive (diffuse expression) to MMP-2 (74% of cases), MMP-9 (49%), TIMP-2 (88%), uPA (89%), uPAR (90%), tPA (69%), and PAI-1 (87%). A weak expression of IL-6 was found in 12% of the adenomas. All reactions were positive (focal expression) in every sample of anterior lobe tissue, except for uPA (negative in 3 out of 9 cases), and IL-6 (faintly positive in 5 out of 8 cases). Adenomas showed remarkably greater expression of uPA than anterior lobe tissue (Chi-square P<0.05). Nonsecreting adenomas exhibited a stronger tendency towards overexpression of uPA in invasive tumours when compared to noninvasive adenomas (Chi-square P=0.053). We found no correlation of MMP-9 expression and tumour invasion. TIMP-2 was overexpressed in noninvasive as compared to invasive adenomas (Chi-square P<0.05). The interrelationship between MMPs and serine proteinases in pituitary adenomas remains to be elucidated. From our data, a correlation between IL-6 and an activation of MMP-9 cannot be proven. The uPA-system may, however, play a role in dural invasion of pituitary adenomas.
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PMID:Expression of serine proteases and metalloproteinases in human pituitary adenomas and anterior pituitary lobe tissue. 1290 90

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

Although many studies have been performed to elucidate the molecular consequences of ultraviolet irradiation, little is known about the effect of infrared radiation on skin aging. In addition to photons, heat is likely to be generated as a consequence of infrared irradiation, and heat shock is widely considered to be an environmental stress. Here we investigated the effect of heat shock on the expressions of matrix metalloproteinase (MMP)-1, MMP-2, and MMP-3 in cultured human skin fibroblasts. Heat shock induced the expression of MMP-1 and MMP-3, but not MMP-2, at the mRNA and protein levels in a temperature-dependent manner, and caused the rapid activation of three distinct mitogen-activated protein kinases (MAPK), extracelluar signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. The heat shock-induced MMP-1 and MMP-3 expression was suppressed by the inhibition of ERK and JNK but not by p38 MAPK inhibition. Furthermore, heat shock increased the synthesis and release of interleukin-6 (IL-6) into culture media. The specific inhibition of IL-6 using a monoclonal antibody against IL-6 greatly reduced the expression of MMP-1 and MMP-3 induced by heat shock. Taken together, our results suggest that ERK and JNK play an important role in the induction of MMP-1 and MMP-3 by heat shock and that the heat shock-induced expression of MMP-1 and MMP-3 is mediated via an IL-6-dependent autocrine mechanism.
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PMID:Heat shock-induced matrix metalloproteinase (MMP)-1 and MMP-3 are mediated through ERK and JNK activation and via an autocrine interleukin-6 loop. 1561 May 7

Metastasis is a multistep process involving a variety of direct cell-cell, cell-matrix and paracrine interactions. In the present study, we examined some consequences of direct interaction between tumour cells and endothelial cells in vitro. When multicellular spheroids of two human tumour cell lines (HeLa and Hep-2) were transferred onto a human umbilical vein endothelial cell (HUVEC) monolayer, a peri-spheroidal zone of damaged endothelial cells was observed after 24h co-culture. To determine the cause of this damage, the production levels of superoxide anion (O2-), interleukin-6 (IL-6) and metalloproteinase-2 (MMP-2) were measured both in co-culture and in monocultures of the tumour cell spheroids and endothelial cells. Attachment of HeLa and Hep-2 cellular spheroids to the HUVEC monolayer resulted in 1.6-fold and 2.1-fold increases in O2- release, respectively. Also, the MMP-2 level was five times greater in the co-culture than in the tumour spheroid monoculture. The increase of IL-6 in the co-culture model, on the other hand, was only slight. However, a 2h preincubation of endothelial cells with LPS (10 microg/ml) prior to the transfer of spheroids induced a significant increase in the production of this cytokine compared to an appropriate control (an LPS-activated endothelial cell monolayer). These results strongly suggest that both ROS and MMP-2 are involved in endothelial cell injury when tumour cells cross the endothelial barrier. Moreover, IL-6, which participates in the inflammatory response, may also be involved in the extravasation of tumour cells.
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PMID:Role of reactive oxygen species (ROS), metalloproteinase-2 (MMP-2) and interleukin-6 (IL-6) in direct interactions between tumour cell spheroids and endothelial cell monolayer. 1589 83

Tumor embolism occurs in 30 to 50% of all cases of cardiac myxoma, but the causes are still uncertain. Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade the extracellular matrix (ECM) and play a crucial role in plaque instability and aortic aneurysm development, in addition to cancer and heart failure. To determine whether MMP activity contributes to tumor embolism, we examined 27 left atrium-sided myxomas, 10 of which showed clinical signs of peripheral embolism. Immunohistochemistry (in all cases) and Western blotting, and in situ and in-gel zymography (in four embolic and six nonembolic consecutive tumors) demonstrated higher expression and activity of MT1-MMP, pro-MMP-2, and pro-MMP-9 in embolic myxomas, whereas pro-MMP-1, MMP-3, and TIMP-1 levels were similar to those of nonembolic tumors. Reverse transcriptase-polymerase chain reaction demonstrated that increased MMP activity was due, at least in part, to increased transcription and that TIMP-2 transcripts increased in embolic myxomas. In vitro, embolic tumor cells retained higher MT1-MMP and pro-MMP-2 levels in basal conditions and after stimulation with interleukin-1beta and interleukin-6. Increased MMP synthesis and release correlated with enhanced ECM degradation products containing glycosaminoglycan chains in embolic myxoma tissue. Our results strongly suggest that MMP overexpression may contribute to an excessive degradation of tumor ECM and increase the risk of embolism in cardiac myxomas.
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PMID:Increased expression and activity of matrix metalloproteinases characterize embolic cardiac myxomas. 1592 Jan 47

Oncostatin M (OSM), a cytokine of the interleukin-6 (IL-6) family, can either promote or inhibit cell growth in various normal and tumor cells. We addressed the effects of exogenous OSM on the proliferation and invasion of human astroglioma cells. In addition, we investigated one of the possible mechanisms involved: modulation of matrix metalloproteinase (MMP) expression and enzymatic activity. We found that OSM inhibited the proliferation of two human astroglioma cell lines (CH235-MG and U87-MG), and that this effect was not due to apoptosis. The inhibitory effect of OSM on proliferation was mediated through the gp130/OSMRbeta receptor complex. To extend these findings, we analyzed the effects of OSM on primary tumor cells from glioblastoma patients. OSM suppressed the proliferation of primary glioblastoma cells, but not that of normal astrocytes. Interestingly, OSM did not suppress astroglioma cell invasion. This may be due to the differential regulation of MMPs by OSM. We found that OSM inhibited the constitutive expression of MMP-2, while MMP-9 expression was enhanced in astroglioma cell lines. We conclude that OSM inhibits proliferation of human astroglioma cells and primary glioblastoma cells via the gp130/OSMRbeta receptor complex. However, OSM does not affect the invasive capacity of the astroglioma cells, which may be due to the divergent effects of OSM on MMP-2 and MMP-9 expression. Collectively, these findings suggest a complex role for OSM in astroglioma biology.
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PMID:Divergent effects of oncostatin M on astroglioma cells: influence on cell proliferation, invasion, and expression of matrix metalloproteinases. 1620 66

Reciprocal interactions between tumor cells and endothelial cells constitute the most important stage of tumor metastasis. There is growing evidence suggesting that beta-estradiol and vitamin D modulate the progression of steroid-sensitive breast cancers. In keeping with those results, the purpose of the study reported here was to determine the cytotoxic and antiproliferative activity of tamoxifen (TAM) in the T47D human breast cancer cell line depending on the cell culture model (three-dimensional (3D, spheroid) or two-dimensional (2D, monolayer)) and to estimate the antiproliferative activity of vitamin D in balanced TAM/beta-estradiol conditions. The study was also designed to investigate whether vitamin D might influence interleukin-6 (IL-6) and metalloproteinase-2 (MMP-2) production in a co-culture of T47D cell spheroids with an endothelial cell monolayer in the presence of beta-estradiol and TAM. Spectrophotometric analysis with MTT revealed that the cytotoxic and antiproliferative activity of TAM was dependent on the culture model, the density of cell culture, and culture medium supplements. In balanced TAM/beta-estradiol medium, vitamin D only slightly inhibited T47D cell proliferation in both 2D and 3D cultures. Direct contact of tumor cell spheroids with the endothelium induced production of MMP-2 and IL-6, which was significantly inhibited in TAM/beta-estradiol balanced medium. Addition of vitamin D further inhibited MMP-2 production, but enhanced the production of IL-6 as was shown by ELISA assay. Our co-culture model in TAM/beta-estradiol balanced medium proved to be useful for examining direct and paracrine interactions of tumor cells with the endothelium in conditions that were closer to in vivo conditions than in the standard 2D model.
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PMID:Vitamin D, tamoxifen and beta-estradiol modulate breast cancer cell growth and interleukin-6 and metalloproteinase-2 production in three-dimensional co-cultures of tumor cell spheroids with endothelium. 1632 60

The enzyme group of matrix metalloproteinases (MMPs) and their inhibitors, so-called tissue inhibitors of matrix-metalloproteinases (TIMPs), are crucial mediators responsible for wound repair after parenchymal damage. Little is known about the role of MMPs and TIMPs in severe sepsis. The aim of the present study was therefore to investigate their levels in patients with severe sepsis and to examine their association with prognosis. MMP-2, MMP-9, TIMP-1, TIMP-2 and interleukin-6 (IL-6) plasma levels were measured by ELISA methods in 37 patients on day 1 of severe sepsis. 37 healthy volunteers served as controls. Levels of MMP-9, TIMP-1, TIMP-2 and IL-6 in septic patients were significantly higher compared to healthy controls (p<0.001), whereas MMP-2 levels were not different in patients and controls. TIMP-1 levels were significantly higher in non-survivors (4675+/-435 ng/ml, mean+/-SEM) compared to survivors of severe sepsis (3201+/-249 ng/ml; p<0.01). Septic patients with TIMP-1 values >3200 ng/ml were 4.5 times more likely to die than patients with lower values (RR = 4.5; 95% CI 1.14-17.6, p = 0.014). Our results indicate that MMP-9, TIMP-2 and TIMP-1 are elevated in severe sepsis. Furthermore, TIMP-1 may serve as a useful laboratory marker to predict the clinical outcome of patients presenting with severe sepsis.
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PMID:Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP-1 in severe sepsis. 1700 30

Western blotting of culture media of myenteric glia stained positive for GFAP revealed increased secretion of matrix metalloproteinase-9 (MMP-9) in interleukin-1beta (IL-1beta) stimulated cells (10 ng/mL) versus control (142 +/- 19 versus 42 +/- 19, P < 0.05). Interleukin-6 (IL-6) stimulated cells also showed increased expression of MMP-9 (10 ng/mL) versus control (69 +/- 14 versus 4 +/- 2, P < 0.01). Control and cytokine-stimulated cells secreted MMP-2 constituitively. Gelatin zymography demonstrated that products were biologically active. Cytoplasmic staining for MMP-9 was detected in IL-1beta and IL-6-stimulated cells but was negligible in controls. Cultured myenteric glia are responsive to IL-1beta and IL-6 stimulation by secreting MMPs into the extracellular environment.
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PMID:Interleukin-1beta and interleukin-6 stimulate matrix metalloproteinase-9 secretion in cultured myenteric glia. 1710 89

The removal of low molecular weight proteins such as beta(2)-microglobulin (beta(2)MG) is accelerated by using a 7.5% icodextrin-based peritoneal dialysis solution (ICO) dwell. To examine the possibility of peritoneal injury in ICO, we investigated the relationship between beta(2)MG and the injury markers in effluent. Sixteen ICO-treated patients (11 male and five female, mean age 50.1 +/- 10.9 years) with continuous ambulatory peritoneal dialysis (CAPD; mean duration 54.6 +/- 30.8 months) were studied. The patients were treated with ICO 2 L and 2.27% glucose-based solution 2 L for an 8-h dwell and the effluent was collected. We investigated the correlations between beta(2)MG and the injury markers (e.g. hyaluronic acid [HA], interleukin-6 [IL-6], matrix metalloproteinase-2 [MMP-2]) in each effluent sample. The beta(2)MG level in the ICO effluent was 8978 +/- 2431 microg/L, significantly higher than in the 2.27% glucose-based solution effluent (6454 +/- 2956 microg/L; P = 0.0032). The levels of HA and MMP-2 in ICO effluent were significantly higher than those in the 2.27% glucose-based solution effluent (P = 0.00214, P = 0.0113, respectively). There was a trend toward higher IL-6-values in ICO effluent, although no significant differences were seen. There were positive correlations between levels of various injury markers and beta(2)MG. We propose that the subclinical injury of the peritoneum by ICO treatment may accelerate peritoneal permeability to increase beta(2)MG in effluent. ICO's biocompatibility might not be superior to that of glucose-based solution.
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PMID:Relationship between effluent levels of beta(2)-microglobulin and peritoneal injury markers in 7.5% icodextrin-based peritoneal dialysis solution. 1766 36


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