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)

Interleukin-6 (IL-6) is involved in angiogenesis. However, the underlying mechanisms are unknown. Using human cerebral endothelial cell (HCEC), we report for the first time that IL-6 triggers HCEC proliferation and migration in a dose-dependent manner, specifically associated with enhancement of VEGF expression, up-regulated and phosphorylated VEGF receptor-2 (KDR), and stimulated MMP-9 secretion. We investigated the signal pathway of IL-6/IL-6R responsible for KDR's regulation. Pharmacological inhibitor of PI3K failed to inhibit IL-6-mediated VEGF overexpression, while blocking ERK1/2 with PD98059 could abolish IL-6-induced KDR overexpression. Further, neutralizing endogenous VEGF attenuated KDR expression and phosphorylation, suggesting that IL-6-induced KDR activation is independent of VEGF stimulation. MMP-9 inhibitor GM6001 significantly decreases HCEC proliferation and migration (p<0.05), indicating the crucial function of MMP-9 in promoting angiogenic changes in HCECs. We conclude that IL-6 triggers VEGF-induced angiogenic activity through increasing VEGF release, up-regulates KDR expression and phosphorylation through activating ERK1/2 signaling, and stimulates MMP-9 overexpression.
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PMID:Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: the role for KDR and MMP-9. 1651 57

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

The tissue inhibitor of metalloproteinases (TIMP)-1 is a multifunctional protein which is not only an inhibitor of matrix metalloproteinases (MMPs) but also to have a possible "cytokine-like" action. Here, we first compared mRNA expression of TIMP-1 and MMP-9 in BEL-7402 (a hepatocellular carcinoma cell line), L-02 (a normal liver cell line) and QSG-7701 (a cell line derived from peripheral tissue of liver carcinoma) using real-time quantitative RT-PCR. By evaluating the variation of the MMP-9/TIMP-1 ratio as an index of reciprocal changes of the expression of the two genes, we observed that the MMP-9/TIMP-1 ratio was about 13- and 5-fold higher in BEL-7402 than in L-02 and QSG-7701, respectively. Significantly, overexpression of TIMP-1 decreased the MMP-9/TIMP-1 ratio in BEL-7402 and then inhibited the cell growth to 60% and reduced the migration to about 30%. Meanwhile, our data showed that interleukin-6 (IL-6) (100 ng/mL) could also inhibited the cell growth of BEL-7402. Further studies indicated that TIMP-1 mediated the inhibitory effect of IL-6 on BEL-7402 cell proliferation in a STAT3-dependent manner, which could further accelerate the expression of the cyclin-dependent kinase inhibitor p21. A dominant negative STAT3 mutant totally abolished IL-6-induced TIMP-1 expression and its biological functions. The present results demonstrate that TIMP-1 may be one of the mediators that regulate the inhibitory effect of IL-6 on BEL-7402 proliferation in which STAT3 signal transduction and p21 up-regulation also play important roles.
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PMID:TIMP-1 mediates the inhibitory effect of interleukin-6 on the proliferation of a hepatocarcinoma cell line in a STAT3-dependent manner. 1746 23

Gastric ulcer is a multifaceted process including acid secretion, reactive oxygen species generation, prostaglandin inhibition, and extracellular matrix (ECM) degradation. Matrix metalloproteinases (MMPs) have the ability to cleave and remodel the ECM. We investigated the activity and expression of MMP-9 and -2 in ethanol-induced acute gastric ulceration in rats. We found that severity of gastric ulcer was strongly correlated with increasing doses of ethanol and increased secretion of proMMP-9. ProMMP-9 was upregulated approximately 25-fold at maximum ulcer index. Increased secretion of proMMP-9 was associated with increased expression of tumor necrosis factor-alpha and interleukin-6. We examined the effect of H(2)-receptor antagonists and antioxidants on proMMP-9 secretion and synthesis during prevention of ethanol-induced gastric ulcer. Our data reveal that famotidine dose dependently blocked increased secretion and synthesis of proMMP-9 during gastroprotection and arrested infiltration of inflammatory cells as well as oxidative stress in rat gastric tissues. Similar to H(2)-receptor antagonists, N-acetylcysteine and dimethyl sulfoxide, well-known antioxidants, inhibited proMMP-9 upregulation to the control level. In conclusion, ethanol-induced gastric ulceration is associated with increased expression of proMMP-9 that can be attenuated by H(2)-receptor antagonists and antioxidants. These findings furnish a novel MMP-9-mediated pathway and its inhibition via proinflammatory cytokines by famotidine in ethanol-induced gastric ulceration.
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PMID:Novel role of famotidine in downregulation of matrix metalloproteinase-9 during protection of ethanol-induced acute gastric ulcer. 1760 38

Malignant ascites is a major source of morbidity and mortality in ovarian cancer patients. It functions as a permissive reactive tumor-host microenvironment and provides sustenance for the floating tumor cells through a plethora of survival/metastasis-associated molecules. Using a syngeneic, immunocompetent model of peritoneal ovarian carcinomatosis in SP(-/-) mice, we investigated the molecular mechanisms implicated in the interplay between host secreted protein acidic and rich in cysteine (SPARC) and ascitic fluid prosurvival/prometastasis factors that result in the significantly augmented levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP). Ascitic fluid-enhanced ID8 invasiveness was mediated through VEGF via a positive feedback loop with MMP-2 and MMP-9 and through activation of alpha(v) and beta(1) integrins. Host SPARC down-regulated the VEGF-MMP axis at the transcriptional and posttranscriptional levels. In vitro, SPARC attenuated the basal as well as VEGF-induced integrin activation in tumor cells. SPARC inhibited the VEGF- and integrin-mediated ID8 proliferation in vitro and significantly suppressed their tumorigenicity in vivo. Relative to SP(+/+), SP(-/-) ascitic fluid contained significantly higher levels of bioactive lipids and exerted stronger chemotactic, proinvasive, and mitogenic effects on ID8 cells in vitro. SP(-/-) ascites also contained high levels of interleukin-6, macrophage chemoattractant protein-1, and 8-isoprostane (prostaglandin F(2)alpha) that were positively correlated with extensive infiltration of SP(-/-) ovarian tumors and ascites with macrophages. In summary, our findings strongly suggest that host SPARC normalizes the microenvironment of ovarian cancer malignant ascites through down-regulation of the VEGF-integrin-MMP axis, decreases the levels and activity of bioactive lipids, and ameliorates downstream inflammation.
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PMID:Normalization of the ovarian cancer microenvironment by SPARC. 1795 2

In atherosclerosis, circulating platelets interact with endothelial cells and monocytes, leading to cell activation and enhanced recruitment of leukocytes into the vascular wall. The invasion of monocytes is accompanied by overexpression of matrix metalloproteinases (MMPs), which are thought to promote atherosclerosis and trigger plaque rupture. Following interaction with itself, the extracellular matrix metalloproteinase inducer (EMMPRIN) induces MMP synthesis via a little-known intracellular pathway. Recently, we showed upregulation of EMMPRIN on monocytes during acute myocardial infarction. EMMPRIN also stimulates secretion of MMP-9 by monocytes and of MMP-2 by smooth muscle cells, indicating that it may be an important regulator of MMP activity. Expression of EMMPRIN on platelets has not been described until now. Here, we demonstrate that resting platelets show low surface expression of EMMPRIN, which is upregulated by various platelet stimulators (flow cytometry). EMMPRIN is located in the open canalicular system and in alpha granules of platelets (according to electron microscopy and sucrose gradient ultracentrifugation). Platelet stimulation with recombinant EMMPRIN-Fc induced surface expression of CD40L and P-selectin (according to flow cytometry), suggesting that EMMPRIN-EMMPRIN interaction activates platelets. Coincubation of platelets with monocytes induced EMMPRIN-mediated nuclear factor kappaB activation (according to Western blot) in monocytes with increased MMP-9 (zymography), interleukin-6, and tumor necrosis factor-alpha secretion (according to ELISA) by monocytes. In conclusion, EMMPRIN displays a new platelet receptor that is upregulated on activated platelets. Binding of EMMPRIN to platelets fosters platelet degranulation. Platelet-monocyte interactions via EMMPRIN stimulate nuclear factor kappaB-driven inflammatory pathways in monocytes, such as MMP and cytokine induction. Thus, EMMPRIN may represent a novel target to diminish the burden of protease activity and inflammation in atherosclerosis.
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PMID:Extracellular matrix metalloproteinase inducer (CD147) is a novel receptor on platelets, activates platelets, and augments nuclear factor kappaB-dependent inflammation in monocytes. 1804 71

Focal cerebral contusion can be dynamic and expansive. It has been proved that subsequent expansive contusion is caused by brain parenchyma damage, especially BBB damage. We investigated a group of patients with traumatic brain injury. The patients (n=18) were divided into group I (n=7) of patients submitted to neurosurgery due to expansive contusion, and group II (n=11) of patients without surgery. Serum concentrations of NSE and S-100B protein were measured by electrochemiluminescence immunoassay, interleukin-6 (IL-6) was measured by chemiluminescent sequential immunometric assay and matrix metalloproteinases (MMP-9, MMP-2) were measured by immunoassays. Cortical biopsy specimens of brain were investigated by electron microscopy in patients with trauma brain injury submitted to neurosurgery. Biochemical investigation from first day up to third day after traumatic brain injury proved increased values of IL-6 (302.2+/-119.9 vs. 59.6+/-11.9 ng/l, p<0.02) and S-100B protein (3.064+/-1.064 vs. 0.649+/-0.182 microg/l, p<0.05) in patients with expansive lesion compared to patients without expansive contusion. Significantly higher levels of MMP-9 (150.4+/-28.46 vs. 74.11+/-13.16 ng/l, p<0.05) and of MMP-2 (814.5+/-126.3 vs. 523.1+/-25.28 ng/l, p<0.05) were found during first 3 days after admission in group I compared to group II. MMP-9 has also elevated in group II from lower values after admission (74.11+/-13.16 ng/l) up to high levels on the 10th day of hospitalization (225.1+/-49.35 ng/l). Ultrastructural investigation of endothelial cells and surrounded tissue revealed perivascular hemorrhage, increased pinocytic activity of endothelial cells, and cytotoxic edema of astroglial cells. Multivesical bodies were disclosed inside the endothelial cells. Higher levels of serum protein S-100B and IL-6 correlated with ultrastructural changes of endothelial cells, and with inflammatory response following TBI, respectively.
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PMID:Correlation of ultrastructural changes of endothelial cells and astrocytes occurring during blood brain barrier damage after traumatic brain injury with biochemical markers of BBB leakage and inflammatory response. 1838 May 46

Duchenne muscular dystrophy (DMD) is a lethal, X-linked disorder associated with dystrophin deficiency that results in chronic inflammation, sarcolemma damage, and severe skeletal muscle degeneration. Recently, the use of L-arginine, the substrate of nitric oxide synthase (nNOS), has been proposed as a pharmacological treatment to attenuate the dystrophic pattern of DMD. However, little is known about signaling events that occur in dystrophic muscle with l-arginine treatment. Considering the implication of inflammation in dystrophic processes, we asked whether L-arginine inhibits inflammatory signaling cascades. We demonstrate that L-arginine decreases inflammation and enhances muscle regeneration in the mdx mouse model. Classic stimulatory signals, such as proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha, are significantly decreased in mdx mouse muscle, resulting in lower nuclear factor (NF)-kappaB levels and activity. NF-kappaB serves as a pivotal transcription factor with multiple levels of regulation; previous studies have shown perturbation of NF-kappaB signaling in both mdx and DMD muscle. Moreover, L-arginine decreases the activity of metalloproteinase (MMP)-2 and MMP-9, which are transcriptionally activated by NF-kappaB. We show that the inhibitory effect of L-arginine on the NF-kappaB/MMP cascade reduces beta-dystroglycan cleavage and translocates utrophin and nNOS throughout the sarcolemma. Collectively, our results clarify the molecular events by which L-arginine promotes muscle membrane integrity in dystrophic muscle and suggest that NF-kappaB-related signaling cascades could be potential therapeutic targets for DMD management.
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PMID:L-arginine decreases inflammation and modulates the nuclear factor-kappaB/matrix metalloproteinase cascade in mdx muscle fibers. 1845 97

Although the actions of cyclosporin (CyA) on keratinocyte are well established, little is known about its effects on dermal fibroblasts. Interleukin-6 (IL-6) is one of the inflammatory cytokines playing a pivotal role in certain skin diseases such as psoriasis. The aim of this study has been to determine whether CyA modifies the metabolism of extracellular matrix (ECM) by human fibroblasts in vitro. CyA altered the morphology of fibroblasts in the collagen matrix. Fibroblast proliferation was suppressed by CyA at 100 and 10 ng/ml. The production of type I collagen and tissue inhibitor of metalloproteinase 1 was also suppressed by CyA at 1000 ng/ml, and co-stimulation with IL-6 enhanced decreased production at 1000 and 100 ng/ml CyA. The production of matrix metalloproteinase 1 (MMP-1) was also suppressed by CyA in a dose-dependent manner. In contrast, the decreased production of MMP-1 was restored at 0.1-100 ng/ml CyA in the presence of IL-6. Regardless of the presence or absence of IL-6, the production of MMP-2 decreased at 1000 and 100 ng/ml, whereas the production of MMP-9 was unchanged. The production of transforming growth factor-beta decreased at 100 ng/ml CyA. This study thus indicates that CyA influences ECM metabolism and the proliferation of human dermal fibroblasts, and that the effects of CyA are modulated by IL-6. CyA might also, in part, improve psoriatic skin by regulating the remodeling of ECM and by its action on immunocompetent cells.
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PMID:Interleukin-6 counteracts effects of cyclosporin A on extracellular matrix metabolism by human dermal fibroblasts. 1855 8

The present study was conducted to compare the renal and vascular protective effects of telmisartan and amlodipine in untreated hypertensive chronic kidney disease (CKD) patients with moderate renal insufficiency. Thirty hypertensive CKD patients were randomly assigned to receive telmisartan 40 mg (n = 15) or amlodipine 5 mg (n = 15) once daily for 12 months. Changes in blood pressure, serum creatinine, 24-h creatinine clearance (Ccr), proteinuria, brachial-ankle pulse wave velocity (baPWV), intima-media thickness (IMT), plasma interleukin-6 (IL-6), plasma matrix metalloproteinase (MMP)-9 and lipid profiles were monitored in all patients. Before treatment, there were no significant differences in these parameters between the telmisartan and amlodipine groups. Over the 12 month observation period, blood pressure decreased equally in both groups. However, serum creatinine, proteinuria, baPWV, IMT, plasma levels of IL-6 and MMP-9 and total cholesterol decreased and 24-h Ccr increased more strikingly in the telmisartan group than the amlodipine group. These data suggest that telmisartan is more effective than amlodipine for protecting renovascular functions, and potentially for ameliorating atherosclerosis, in hypertensive CKD patients with moderate renal insufficiency.
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PMID:Comparison of renal and vascular protective effects between telmisartan and amlodipine in hypertensive patients with chronic kidney disease with mild renal insufficiency. 1913 8


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