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)

We have reported that prostaglandin F2alpha (PGF2alpha) stimulates the synthesis of vascular endothelial growth factor (VEGF) via p44/p42 mitogen-activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells. In addition, we recently showed that phosphatidylinositol 3 (PI3)-kinase activated by platelet-derived growth factor-BB (PDGF-BB) negatively regulates the interleukin-6 synthesis in these cells. In the present study, we investigated the effect of PDGF-BB on the PGF2alpha-induced VEGF synthesis in MC3T3-E1 cells. PDGF-BB, which alone did not affect the levels of VEGF, significantly enhanced the PGF2alpha-stimulated VEGF synthesis. The amplifying effect of PDGF-BB was dose dependent in the range between 10 and 70 ng/ml. LY294002 or wortmannin, specific inhibitors of PI3-kinase, which by itself failed to affect the PGF2alpha-stimulated VEGF synthesis, significantly suppressed the amplification by PDGF-BB. PD98059, a specific inhibitor of MEK1/2, suppressed the amplification by PDGF-BB of the PGF2alpha-stimulated VEGF synthesis similar to the levels of PGF2alpha with PD98059. PDGF-BB itself induced the phosphorylation of p44/p42 MAP kinase in these cells, and the effects of PDGF-BB and PGF2alpha on the phosphorylation of p44/p42 MAP kinase were additive. Moreover, LY294002 had little effect on the phosphorylation of p44/p42 MAP kinase induced by PGF2alpha with PDGF-BB. These results strongly suggest that PGF2alpha-stimulated VEGF synthesis is amplified by PI3-kinase-mediating PDGF-BB signaling in osteoblasts, and that the effect is exerted at a point downstream from p44/p42 MAP kinase.
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PMID:Platelet-derived growth factor-BB amplifies PGF2alpha-stimulated VEGF synthesis in osteoblasts: function of phosphatidylinositol 3-kinase. 1798 May 68

We previously showed that basic fibroblast growth factor (FGF-2) activates the mitogen-activated protein (MAP) kinase superfamily in osteoblast-like MC3T3-E1 cells and that p38 MAP kinase functions as a positive regulator in the FGF-2-stimulated synthesis of interleukin-6 (IL-6), a potent bone-resorptive agent, in these cells. In the present study, we investigated the exact mechanism of IL-6 and the effects of (-)-epi-gallocatechin gallate (EGCG), one of the major green tea flavonoids, on the synthesis of IL-6. PD98059, an inhibitor of MEK, but not SP600125, an inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase, suppressed FGF-2-stimulated IL-6 synthesis. EGCG significantly reduced the IL-6 synthesis stimulated by FGF-2 in a dose-dependent manner. EGCG attenuated the FGF-2-induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase. These results strongly suggest that EGCG inhibits the FGF-2-stimulated synthesis of IL-6 at least partly via suppression of the p44/p42 MAP kinase pathway and the p38 MAP kinase pathway in osteoblasts.
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PMID:(-)-Epigallocatechin gallate inhibits basic fibroblast growth factor-stimulated interleukin-6 synthesis in osteoblasts. 1850 Jun 74

We have previously reported that prostaglandin F(2alpha) (PGF(2alpha)) stimulates interleukin-6 (IL-6), a potent bone resorptive agent, through p44/p42 mitogen-activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether Rho-kinase is implicated in the PGF(2alpha)-stimulated IL-6 synthesis in MC3T3-E1 cells. PGF(2alpha) time-dependently induced the phosphorylation of myosin phosphatase targeting subunit (MYPT-1), a Rho-kinase substrate. Y27632, a specific Rho-kinase inhibitor, significantly reduced the PGF(2alpha)-stimulated IL-6 synthesis as well as the MYPT-1 phosphorylation. Fasudil, another inhibitor of Rho-kinase, suppressed the PGF(2alpha)-stimulated IL-6 synthesis. Y27632 and fasudil failed to affect the PGF(2alpha)-induced phosphorylation of p44/p42 MAP kinase. SB203580 and BIRB0796, potent inhibitors of p38 MAP kinase, suppressed the IL-6 synthesis induced by PGF(2alpha). While SP600125, an inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), failed to reduce the synthesis. Y27632 as well as fasudil attenuated the PGF(2alpha)-induced phosphorylation of p38 MAP kinase. These results strongly suggest that Rho-kinase regulates PGF(2alpha)-stimulated IL-6 synthesis via p38 MAP kinase activation in osteoblasts.
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PMID:Involvement of Rho-kinase in prostaglandin F2alpha-stimulated interleukin-6 synthesis via p38 mitogen-activated protein kinase in osteoblasts. 1858 82

We have previously reported that prostaglandin D2 (PGD2) stimulates interleukin-6 (IL-6), a potent bone resorptive agent, in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether Rho-kinase is implicated in the PGD2-stimulated IL-6 synthesis in MC3T3-E1 cells. PGD2 time-dependently induced the phosphorylation of myosin phosphatase targeting subunit (MYPT-1), a Rho-kinase substrate. Y27632, a specific Rho-kinase inhibitor, significantly reduced the PGD2-stimulated IL-6 synthesis as well as the MYPT-1 phosphorylation. Fasudil, another inhibitor of Rho-kinase, suppressed the PGD2-stimulated IL-6 synthesis. The PGD2-stimulated IL-6 synthesis was reduced by PD98059, a MEK inhibitor, and SB203580, an inhibitor of p38 mitogen-activated protein (MAP) kinase, but not SP600125, an inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). However, Y27632 and fasudil failed to affect the PGD2-induced phosphorylation of p44/p42 MAP kinase. On the other hand, Y27632 as well as fasudil markedly attenuated the PGD2-induced phosphorylation of p38 MAP kinase. In addition, PGD2 additively induced IL-6 synthesis in combination with endothelin-1 which induces IL-6 synthesis through p38 MAP kinase regulated by Rho-kinase. These results strongly suggest that Rho-kinase regulates PGD2-stimulated IL-6 synthesis via p38 MAP kinase activation in osteoblasts.
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PMID:Function of Rho-kinase in prostaglandin D2-induced interleukin-6 synthesis in osteoblasts. 1877 7

Interleukin-6 (IL-6) is involved in a variety of biological responses, including the glucose metabolism and cell growth, which is a critical physiological function requiring multiple metabolic pathways. Therefore, in the present study, we examined the effect of IL-6 on 2-deoxyglucose (2-DG) uptake and the related signaling pathways in primary cultured chicken hepatocytes. IL-6 increased 2-DG uptake in a time- (> or =4 h) and a dose -(> or =5 ng/ml) dependent manner. Indeed, IL-6 increased GLUT-2 mRNA and protein expression as well as 2-DG uptake, which were blocked by actinomycin D (AD, transcription inhibitor) and cycloheximide (CHX, translation inhibitor). IL-6 (10 ng/ml) increased the level of IL-6Ralpha and glycoprotein (gp) 130 (IL-6Rbeta) protein expressions. IL-6 increased Janus Kinase (JAK)-2, signal transducer and activator of transcription (STAT)-3 phosphorylation, intracellular Ca(2+) concentration, and PKC phosphorylation. IL-6-induced increase of 2-DG uptake and GLUT-2 protein expression were blocked by JAK2-specific siRNA, a STAT3 inhibitor, staurosporine, and bisindolylmaleimide I (PKC inhibitors). In addition, IL-6 increased EGFR/src/FAK, PI3K/Akt phosphorylation and 2-DG uptake as well as GLUT-2 protein expression, which were blocked by AG 1478 (EGF receptor inhibitor), PP2 (src family of tyrosine kinase inhibitor), PI3K-specific siRNA, and a Akt inhibitor. Furthermore, IL-6 increased p44/42 MAPKs phosphorylation and p44 and p42 MAPK-specific siRNA mixture blocked IL-6-induced increase of 2-DG uptake and GLUT-2 protein expression. In conclusion, IL-6 stimulates the 2-DG uptake through p44/42 MAPKs activation via Ca(2+)/PKC and EGF receptor in primary cultured chicken hepatocytes.
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PMID:Interleukin-6 promotes 2-deoxyglucose uptake through p44/42 MAPKs activation via Ca2+/PKC and EGF receptor in primary cultured chicken hepatocytes. 1900 19

We previously showed that the mitogen-activated protein (MAP) kinase superfamily, p44/p42 MAP kinase, p38 MAP kinase, and stress-activated protein kinase (SAPK)/c-Jun N-terminal (JNK), positively plays a part in the platelet-derived growth factor-BB- (PDGF-BB-) stimulated synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, in osteoblast-like MC3T3-E1 cells while Akt and p70 S6 kinase negatively regulates the synthesis. In the present study, we investigated whether (-)-epigallocatechin gallate (EGCG), one of the major green tea flavonoids, affects the synthesis of IL-6 in these cells and the mechanism. EGCG significantly reduced the IL-6 synthesis and IL-6 mRNA expression stimulated by PDGF-BB, EGCG reduced the PDGF-BB-stimulated IL-6 synthesis also in primary-cultured osteoblasts. EGCG had no effect on the levels of osteocalcin and osteoprotegerin in MC3T3-E1 cells. The PDGF-BB-induced autophosphorylation of PDGF receptor beta was not suppressed by EGCG. The PDGF-BB-induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was not affected by EGCG. On the other hand, EGCG markedly suppressed the PDGF-BB-induced phosphorylation of SAPK/JNK. Finally, the PDGF-BB-induced phosphorylation of Akt and p70 S6 kinase was not affected by EGCG. These results strongly suggest that EGCG inhibits the PDGF-BB-stimulated synthesis of IL-6 via suppression of SAPK/JNK pathway in osteoblasts.
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PMID:(-)-Epigallocatechin gallate reduces platelet-derived growth factor-BB-stimulated interleukin-6 synthesis in osteoblasts: suppression of SAPK/JNK. 1914 96

Previous investigations have shown the immunosuppressive activity of the immunophilin-binding macrolide Sanglifehrin A (SFA). In adults, SFA also exerts anti-inflammatory properties in lipopolysaccharide (LPS)-stimulated whole blood cultures. It was the aim of this study to investigate whether the unique properties of SFA are also present in the neonatal immune system, as neonates are susceptible to serious infection due to an immaturity of immune responses. We used a whole blood assay to investigate the impact of SFA on T-cell proliferation and secretion of T-cell cytokines upon Anti-CD3/Anti-CD28 costimulation. In addition, interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha) secretion was assessed in whole blood monocytes after LPS stimulation. Furthermore, the influence of SFA on LPS-induced signal transduction pathways, specifically the activity of p42/44, p38 and Ap-1, was assessed in neonatal PBMCs. Neonatal cord blood lymphocytes were found to have a diminished IL-4, IL-6, TNF-alpha and interferon-gamma (IFN-gamma) production upon Anti-CD3/Anti-CD28 costimulation compared to adult whole blood lymphocytes. In contrast, no significant differences were noted for either IL-2 production or proliferation of CD4+ cells. Upon addition of 1000nM SFA to neonatal whole blood cultures, a significant inhibition of both, T-cell cytokine secretion and proliferation was demonstrated. In line with data from adult whole blood cultures, SFA proved to be a strong inhibitor of LPS-induced expression of IL-6 and TNF-alpha in the neonatal whole blood system. In signal transduction studies of the LPS pathway, a potent inhibition of the protein kinase p42/44 was demonstrated. SFA was also shown to block nuclear translocation of the transcription factor Ap-1. SFA was proved to have inhibitory effects on innate and acquired immune response of neonatal whole blood cells. The protein kinase p42/44 and the transcription factor Ap-1 were demonstrated to be potential key molecules for the anti-inflammatory effect of SFA.
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PMID:Immunomodulatory effects of Sanglifehrin A in the innate and acquired immune response of neonatal whole blood cells. 1921 6

Our previous study demonstrated that tumor necrosis factor-alpha (TNF-alpha) stimulates the synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase/Akt in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether p70 S6 kinase is involved in TNF-alpha-stimulated IL-6 synthesis in MC3T3-E1 cells. TNF-alpha time dependently induced the phosphorylation of p70 S6 kinase. Rapamycin, an inhibitor of p70 S6 kinase, which attenuated the phosphorylation of p70 S6 kinase induced by TNF-alpha, significantly amplified the TNF-alpha-stimulated IL-6 synthesis. TNF-alpha-induced phosphorylations of both p44/p42 MAP kinase and Akt were markedly enhanced by rapamycin. The amplification by rapamycin of TNF-alpha-induced IL-6 synthesis was reduced by PD98059, a specific inhibitor of MEK1/2, or Akt inhibitor. Rapamycin enhanced the IL-6 synthesis and the phosphorylation of Akt induced by TNF-alpha also in human osteoblasts. Taken together, these results strongly suggest that p70 S6 kinase limits the TNF-alpha-stimulated IL-6 synthesis at a point upstream from p44/p42 MAP kinase and Akt in osteoblast-like cells.
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PMID:p70 S6 kinase limits tumor necrosis factor-alpha-induced interleukin-6 synthesis in osteoblast-like cells. 1987 24

Fibroblast growth factor-2 (FGF-2) is highly expressed in prostate cancer. It promotes tumour progression through multiple pathways including those of signal transducers and activators of transcription factor 3 (STAT3), mitogen-activated protein kinases (MAPKs) and Akt. In previous studies, we have reported that STAT3 phosphorylation inversely correlates with suppressor of cytokine signalling-3 (SOCS-3) expression in prostate cancer cells. Recently, it has become evident that SOCS-3-negative regulation is not only limited to the interleukin-6 (IL-6) receptor. We hypothesised that SOCS-3 interferes with FGF signalling, thus influencing the outcome of its action in prostate cancer cells. For this purpose, we treated DU-145 and LNCaP-IL-6+ cells with increasing concentrations of FGF-2, and verified protein phosphorylation. In the presence of FGF-2, neither STAT3, STAT1, nor Akt could be phosphorylated. Solely the p44/p42 MAPK pathway was activated after FGF-2 stimulation. We show for the first time that SOCS-3 interferes with the FGF-2 signalling pathway by modulating p44 and p42 phosphorylation in prostate cancer cells. Decreased SOCS-3 protein expression results in increased MAPK phosphorylation, whereas SOCS-3 overexpression leads to a decreased cellular proliferation and migration. On the basis of the present results, we propose that SOCS-3 is a novel modulator of FGF-2-regulated cellular events in prostate cancer.
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PMID:SOCS-3 antagonises the proliferative and migratory effects of fibroblast growth factor-2 in prostate cancer by inhibition of p44/p42 MAPK signalling. 2033 9

Interleukin-6 (IL-6) is a growth and survival factor in human glioblastoma cells and plays an important role in malignant progression. However, its role in glioblastoma invasion is still unknown. This study shows how IL-6 promotes cell invasion and migration in U251 and T98G glioblastoma cell lines. The underlying mechanism includes both protease-dependent and -independent manners. Stimulation with IL-6 increased MMP9 expression in the two cell lines but had no influence on MMP2 expression. Fascin-1 is a cell skeleton binding protein and plays a key role in cell migration and invasion. Its binding style directly influences cell morphology and tendency to become deformed. After IL-6 exposure, fascin-1 expression increased in an IL-6 dose-dependent manner. Immunofluorescence also revealed that the binding style of fascin-1 had changed after IL-6 exposure, resulting in a more invasive phenotype of the cells. Three most commonly emphasized invasion-associated signaling pathways, including JAK-STAT3, p42/44 MAPK, and PI3K/AKT, were verified to further illustrate its underlying mechanism. Only phosphorylation of STAT3 at ser 727 site paralleled the IL-6 stimulation, and JSI-124, a specific JAK-STAT3 pathway blocker, deterred the invasion and migration promotive effect of IL-6, indicating that the JAK/STAT3 pathway mediates signal transduction. Furthermore, IL-6 also acts in a paracrine fashion to promote vascular endothelial cell migration, thus facilitating tumor angiogenesis and invasion. These results suggest that IL-6 promotes glioblastoma cell invasion and angiogenesis and may be a potential anti-invasion target.
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PMID:IL-6 promotion of glioblastoma cell invasion and angiogenesis in U251 and T98G cell lines. 2036 49


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