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)

Melanophores of the isolated tail fin of the Xenopus tadpole aggregate melanin granules in response to light. This aggregation was found to be inhibited by subcutaneous injection of exoenzyme C3 of Clostridium botulinum. A 26 kDa protein in homogenate obtained from the Xenopus tail fin was ADP-ribosylated by exoenzyme C3. This reaction was inhibited effectively by a monoclonal antibody, anti-Rho mab A5. raised against the small GTP-binding protein Rho. The extent of ADP-ribosylation depended on light and guanine nucleotide. Incubation under illumination partly reduced ADP-ribosylation and the reduction was restored by addition of guanine nucleotide during incubation. These findings suggest that Rho is involved in the photo-sensitive melanophore response as a signal transducer linking photo-stimuli to melanin granule translocation with Xenopus melanophores.
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PMID:Light-sensitive response in melanophores of Xenopus laevis: II.Rho is involved in light-induced melanin aggregation. 890 75

While investigating endonucleases potentially involved in apoptosis, an antisera was raised to bovine deoxyribonuclease II, but it recognized a smaller protein of 26 kDa protein in a variety of cell lines. The 26 kDa protein underwent proteolytic cleavage to 22 kDa concomitantly with DNA digestion in cells induced to undergo apoptosis. Sequencing of the 26 kDa protein identified it as the Rho GDP-dissociation inhibitor D4-GDI. Zinc, okadaic acid, calyculin A, cantharidin, and the caspase inhibitor z-VAD-fmk, all prevented the cleavage of D4-GDI, DNA digestion, and apoptosis. The 26 kDa protein resided in the cytoplasm of undamaged cells, whereas following cleavage, the 22 kDa form translocated to the nucleus. Human D4-GDI, and D4-GDI mutated at the caspase 1 or caspase 3 sites, were expressed in Chinese hamster ovary cells which show no detectable endogenous D4-GDI. Mutation at the caspase 3 site prevented D4-GDI cleavage but did not inhibit apoptosis induced by staurosporine. The cleavage of D4-GDI could lead to activation of Jun N-terminal kinase which has been implicated as an upstream regulator of apoptosis in some systems. However, the results show that the cleavage of D4-GDI and translocation to the nucleus do not impact on the demise of the cell.
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PMID:Cleavage and nuclear translocation of the caspase 3 substrate Rho GDP-dissociation inhibitor, D4-GDI, during apoptosis. 1038 42

Cyclooxygenase-2 (COX-2) is not normally expressed in the human large intestine, but its levels are increased in the majority of human colorectal carcinomas. Here we investigate the regulation of constitutive COX-2 expression and prostaglandin production in human colorectal carcinoma cells. Both COX-2 mRNA and protein were expressed in well differentiated HCA-7, Moser, LS-174, and HT-29 cells, albeit at different levels. COX-2 expression was not detected in several poorly differentiated colon cancer cell lines including DLD-1. Transcriptional regulation played a key role for the expression of COX-2 in human colon carcinoma cells, and both the nuclear factor for interleukin-6 regulatory element and the cAMP-response element were responsible for regulation of COX-2 transcription. COX-2 mRNA was more stable in HCA-7 cells than in the other cell lines tested. Both transcriptional and post-transcriptional regulation of COX-2 involved the MAP kinase pathway. Modulation of the Akt/protein kinase B or Rho B signaling pathways altered the levels of COX-2 expression. Furthermore, COX-2 protein is degraded through ubiquitin proteolysis, and its half-life was approximately 3.5-8 h. HCA-7 cells produced significant quantities of prostaglandin E(2) and other prostaglandins. Moser and LS-174 cells also generated prostaglandins, but levels were significantly lower than that observed in HCA-7 cells.
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PMID:Regulation of constitutive cyclooxygenase-2 expression in colon carcinoma cells. 1093 Apr 1

Interleukin-6 (IL-6) is a key molecule in chronic inflammation and has been implicated in the progression of atherosclerosis. HMG-CoA reductase inhibitors (statins) may reduce the cardiovascular risk and vulnerability of atherosclerotic plaque through nonlipid as well as lipid-lowering mechanisms, but their anti-inflammatory effects on the vascular tissue have not been fully elucidated. We investigated the effects of fluvastatin on IL-6 synthesis in human vascular smooth muscle cells (VSMCs). Addition of fluvastatin decreased IL-6 synthesis in VSMCs in a time (0-24 hours)- and dose (10(-8)-10(-5) mol/L)-dependent manner. Fluvastatin also decreased IL-6 mRNA expression in VSMCs. The effects of fluvastatin on IL-6 expression were completely reversed in the presence of mevalonate or geranylgeranyl-pyrophosphate, but not squalene. Inhibition of Rho by C3 exoenzyme or Rho kinase by Y-27632 significantly decreased IL-6 expression in VSMCs. In conclusion, fluvastatin decreases IL-6 synthesis in human VSMCs through inhibition of Rho pathway. These findings suggested that reduction of IL-6 expression by statins may partially explain their therapeutic effects in patients with coronary artery disease.
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PMID:HMG-CoA reductase inhibitors reduce interleukin-6 synthesis in human vascular smooth muscle cells. 1209 Sep 4

Uropathogenic Escherichia coli strains frequently produce a Rho-activating protein toxin named cytotoxic necrotizing factor type 1 (CNF1). We herein report that CNF1 promotes transcription and release of tumor necrosis factor alpha, gamma interferon, interleukin-6 (IL-6), and IL-8 proinflammatory cytokines and increases the production of reactive oxygen species (ROS) in uroepithelial T24 cells. The antioxidant N-acetyl-L-cysteine counteracts these phenomena, a fact which suggests a role for ROS-mediated signaling in CNF1-induced proinflammatory cytokine production.
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PMID:Cytotoxic necrotizing factor 1 enhances reactive oxygen species-dependent transcription and secretion of proinflammatory cytokines in human uroepithelial cells. 1281 13

The designation of atherosclerosis as a chronic inflammatory process represents an interesting paradigmatic shift for cardiologists. The plasma concentrations of interleukin-6 and its hepatic byproduct, C-reactive protein, may reflect the intensity of occult plaque inflammation and the vulnerability to rupture. Monocyte chemoattractant protein-1 and interleukin-8 play a crucial role in initiating atherosclerosis by recruiting monocytes/macrophages to the vessel wall, which promotes atherosclerotic lesions and plaque vulnerability. In addition, circulating levels of these proinflammatory cytokines increase in patients with acute myocardial infarction and unstable angina, but not in those with stable angina. Also, the plasma concentrations of these cytokines increase after percutaneous coronary intervention, causing late restenosis after the procedure. Angiotensin II and other atherogenic factors induce these cytokines in the cardiovascular tissues through the activation of transcription factors, such as nuclear factor-kappaB or peroxisome proliferator-activated receptors. Conversely, HMG-CoA reductase inhibitors (statins) can potently inhibit these proinflammatory factors in the vessels. A small GTP-binding protein, Rho, may be a key molecule to explain the anti-inflammatory effects of statins. Interleukin-10 also exerts anti-inflammatory effects on the cardiovascular tissues, possibly by deactivating proinflammatory cytokines and inducible nitric oxide synthase. Gene therapy using interleukin-10 may be a promising means for untreatable or complicated cases of cardiovascular diseases. Thus, therapeutic modulations of these inflammatory cytokines may be useful in the prevention of atherosclerosis and future cardiovascular events.
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PMID:Inflammatory cytokines and cardiovascular disease. 1456 Nov 60

Rho family GTPases and STAT3 act as mediators of cytokine and growth factor signaling in a variety of cellular functions involved in inflammation, tumorigenesis, and development. In the course of searching for their functional connections, we found by using STAT3 knock-out mouse embryonic fibroblasts that RhoA, Rac1, and Cdc42 could cause nonspecific activation of STAT3 promoter-driven luciferase reporter in the absence of STAT3, raising concerns to a body of literature where STAT3 was associated with Rho GTPases based on the reporter system. We also found that although active RhoA, Rac1, and Cdc42 could all mediate Ser-727 and Tyr-705 phosphorylation and nuclear translocation of STAT3, the Rho GTPases were able to induce STAT3 activation independently of the interleukin-6 autocrine pathway, and active RhoA, Rac1, or Cdc42 could not form a stable complex with STAT3 as previously suggested, indicating an unappreciated mechanism of STAT3 activation by the Rho GTPases. The RhoA-induced STAT3 activation partly depended on Rho-associated kinase (ROK) and involved multiple effector signals as revealed by the examination of effector domain mutants of RhoA. Genetic deletion of STAT3 led to a loss of response to RhoA in myosin light chain phosphorylation and actin stress fiber induction but sensitized the cells to RhoA or ROK-stimulated cell migration. STAT3 was required for the RhoA-induced NF-kappaB and cyclin D1 transcription and was involved in NF-kappaB nuclear translocation. Furthermore, loss of STAT3 expression inhibited RhoA-promoted cell proliferation and blocked RhoA or ROK induced anchorage-independent growth. These phenotypic changes in STAT3-/- cells could be rescued by reconstituting STAT3 gene. Our studies carried out in STAT3 null cells demonstrate unambiguously that STAT3 represents an essential effector pathway of Rho GTPases in regulating multiple cellular functions including actin cytoskeleton reorganization, cell migration, gene activation, and proliferation.
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PMID:A role of STAT3 in Rho GTPase-regulated cell migration and proliferation. 1570 84

Human plasma membrane-associated sialidase (NEU3), specifically hydrolyzing gangliosides, plays crucial roles in the regulation of cell surface functions. Here we demonstrate that NEU3 mRNA level are increased in renal cell carcinomas (RCCs) compared with adjacent non-tumor tissues, significantly correlating with elevation of interleukin-6 (IL-6), a pleiotropic cytokine that has been implicated in immune responses and pathogenesis of several cancers, including RCCs. In human RCC ACHN cells, IL-6 treatment enhanced NEU3 promoter luciferase activity 2.5-fold and the endogenous sialidase activity significantly. NEU3 transfection or IL-6 treatment resulted in both suppression of apoptosis and promotion of cell motility, and the combination had synergistic effects. NEU3 scarcely affected MAPK- or IL-6-induced STAT3 activation but promoted the phosphatidylinositol 3-kinase (PI3K)/Akt cascade in both IL-6-dependent and -independent ways. Consistent with these data, NEU3 markedly inhibited staurosporine-induced caspase-3 activity and enhanced IL-6-dependent inhibition, which was abolished by LY294002, a PI3K inhibitor. Furthermore, IL-6 promoted Rho activation, and the effect was potentiated by NEU3, leading to increased cell motility that was again affected by LY294002. NEU3 silencing by siRNA resulted in the opposite: decreased Akt phosphorylation and inhibition of Rho activation. Glycolipid analysis showed a decrease in ganglioside GM3 and increase in lactosylceramide after NEU3 transfection, with these lipids apparently affecting cell apoptosis and motility. The results indicate that NEU3 activated by IL-6 exerts IL-6-mediated signaling, largely via the PI3K/Akt cascade, in a positive feedback manner and contributes to expression of a malignant phenotype in RCCs. NEU3 thus may be a useful target for RCC diagnosis and therapy.
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PMID:Plasma membrane-associated sialidase is up-regulated in renal cell carcinoma and promotes interleukin-6-induced apoptosis suppression and cell motility. 1642 83

We have previously reported that endothelin-1 (ET-1) stimulates interleukin-6 (IL-6), a potent bone resorptive agent, through p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the involvement of Rho-kinase in the ET-1-stimulated IL-6 synthesis in MC3T3-E1 cells. ET-1 time-dependently induced the phosphorylation of myosin phosphatase targeting subunit (MYPT-1), a Rho-kinase substrate. Y27632, a specific inhibitor of Rho-kinase, significantly suppressed the IL-6 synthesis induced by ET-1 as well as the MYPT-1 phosphorylation. Fasudil, another inhibitor of Rho-kinase, reduced the ET-1-stimulated IL-6 synthesis. Y27632 as well as fasudil attenuated the ET-1-induced phosphorylation of p38 MAP kinase but not p44/p42 MAP kinase. These results strongly suggest that Rho-kinase regulates ET-1-stimulated IL-6 synthesis through p38 MAP kinase activation in osteoblasts.
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PMID:Rho-kinase regulates endothelin-1-stimulated IL-6 synthesis via p38 MAP kinase in osteoblasts. 1782 50

Inflammatory activation of the endothelium by Chlamydophila pneumoniae infection has been implicated in the development of chronic vascular lesions and coronary heart disease by seroepidemiological and animal studies. We tested the hypothesis that C. pneumoniae induced inflammatory gene expression is regulated by Rho-GTPase-related histone modifications. C. pneumoniae infection induced the liberation of proinflammatory interleukin-6, interleukin-8, granulocyte colony-stimulating factor, macrophage inflammatory protein-1beta, granulocyte/macrophage colony-stimulating factor, and interferon-gamma by human endothelial cells. Cytokine secretion was reduced by simvastatin and the specific Rac1 inhibitor NSC23766 but was synergistically enhanced by inhibitors of histone deacetylases trichostatin A and suberoylanilide hydroxamic acid. Infection of endothelial cells with viable C. pneumoniae, but not exposure to heat-inactivated C. pneumoniae or infection with C. trachomatis, induced acetylation of histone H4 and phosphorylation and acetylation of histone H3. Pretreatment of C. pneumoniae-infected cells with simvastatin or NSC23766 reduced global histone modifications as well as specific modifications at the il8 gene promoter, as shown by chromatin immunoprecipitation. Reduced recruitment of nuclear factor kappaB p65/RelA as well as of RNA polymerase II was observed in statin-treated cells. Taken together, Rac1-mediated histone modifications seem to play an important role in C. pneumoniae-induced cytokine production by human endothelial cells.
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PMID:Simvastatin reduces Chlamydophila pneumoniae-mediated histone modifications and gene expression in cultured human endothelial cells. 1843 97


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