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)

Numerous reports suggest that interleukin-6 (IL-6) promotes survival and proliferation of tumor cells through the phosphorylation of a cell-signaling protein, signal-transducer-and-activator-of-transcription-3 (STAT3). Constitutive activation of STAT3 in head and neck squamous cell carcinoma (HNSCC) and its role in proliferation of this tumor has been demonstrated. Thus, agents that can suppress STAT3 activation have potential for the treatment of HNSCC. In the present report, we demonstrate that most HNSCC cell lines had constitutively active STAT3 and that curcumin (diferuloylmethane), a pharmacologically safe agent in humans, inhibited STAT3 phosphorylation in a dose- and time-dependent manner. Nuclear translocation of STAT3 was also inhibited by curcumin. The inhibition of STAT3 activation by curcumin was reversible, although even 24 hr after curcumin removal, only partial reversal occurred. Besides inhibiting constitutive expression, curcumin also abrogated the IL-6-induced activation of STAT3 in HNSCC cells. When compared with AG490, a well-characterized JAK2 inhibitor, curcumin was more rapid (30 min vs. 4 hr) and more potent (25 microM vs. 100 microM) inhibitor of STAT3 phosphorylation. Curcumin was also a more potent inhibitor of HNSCC cell proliferation than AG490. Overall, our results demonstrated that curcumin is a potent inhibitor of constitutive and IL-6-induced STAT3 phosphorylation. This mechanism may be at least partially responsible for curcumin's ability to suppress proliferation of HNSCC cells.
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PMID:Targeting constitutive and interleukin-6-inducible signal transducers and activators of transcription 3 pathway in head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane). 1664 80

Increased levels of interleukin-6 (IL-6) play a role in post-ischemic cerebral inflammation. IL-6 binding to its receptors induces phosphorylation of the receptor associated janus kinases (JAKs), and the down-stream signal transducer and activator of transcription (STAT) family of transcription factors, which amplify the IL-6 signal transduction. We evaluated the functional significance of JAK2 and STAT3 activation in focal ischemia-induced neuronal damage. Transient middle cerebral artery occlusion in adult rats led to increased JAK2 and STAT3 phosphorylation in the ipsilateral cortex and striatum after 6-72 h of reperfusion. Fluorescent immunohistochemistry with cell specific markers (NeuN for neurons, glial fibrillary acidic protein for reactive astrocytes and ED1/OX42 for activated macrophages/microglia) showed that both pJAK2 and pSTAT3 staining is predominantly localized in the macrophages/microglia in the post-ischemic brain. Intracerebroventricular infusion of rats with AG490 (a JAK2 phosphorylation inhibitor) prevented the post-ischemic JAK2 and STAT3 phosphorylation and significantly decreased the infarct volume, number of apoptotic cells and neurological deficits, compared to vehicle control. Furthermore, intracerebral injection of siRNA specific for STAT3 led to curtailed STAT3 mRNA expression and phosphorylation, decreased infarct volume, fewer apoptotic cells and improved neurological function following transient middle cerebral artery occlusion. These studies show that JAK2-STAT3 activation plays a role in post-ischemic brain damage.
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PMID:JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia. 1692 54

The role of Janus-activated kinase (JAK) signaling in cell cycle transit and maintenance of genomic stability was determined in HL-60 myeloblastic leukemia cells. Inhibition of JAKs, all JAKs (JAK1, JAK2, JAK3, and tyrosine kinase 2), JAK2, or JAK3, caused a significant reduction in cell growth with a major G2-M arrest evident 24 hours after treatment. Targeting all JAKs also caused endoreduplication 48 and 72 hours after treatment. We discovered mitotic cells in both G2 (4N DNA) and G4 (8N DNA) subpopulations of cells treated with an inhibitor of all JAKs as detected by phosphorylated histone H3 expression. Treatment with inhibitors of just JAK2 or JAK3 drastically reduced such mitotic cells. We observed a complete blockage of IFN-gamma and interleukin-6-induced signal transducer and activator of transcription (STAT)-1 and STAT-3 response when all JAKs were inhibited. At the same time, we found baseline phosphorylated extracellular signal-regulated kinase (ERK) 1/2 to be elevated by JAK inhibition, particularly when all JAKs were inhibited. The G2-M arrest and endoreduplication induced by JAK inhibitors were reduced in cells pretreated with PD98059 to inhibit ERK. PD98059 also increased back the expression of the MAD2 cell cycle checkpoint protein that was down-regulated during "all JAKs inhibitor"-mediated endoreduplication. These data suggest that JAK signaling is needed for G2-M transit with inhibition of ERK.
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PMID:Inhibition of the janus kinase family increases extracellular signal-regulated kinase 1/2 phosphorylation and causes endoreduplication. 1698 50

A conditioning lesion to peripheral axons of primary sensory neurons accelerates regeneration of their central axons in vivo or neurite outgrowth if the neurons are grown in vitro. Previous evidence has implicated neuropoietic cytokines and also cyclic AMP in regenerative conditioning. In experiments reported here, delivery through a lentivirus vector of ciliary neurotrophic factor to the appropriate dorsal root ganglion in rats was sufficient to mimic the conditioning effect of peripheral nerve injury on the regeneration of dorsal spinal nerve root axons. Regeneration in this experimental preparation was also stimulated by intraganglionic injection of dibutyryl cyclic AMP but the effects of ciliary neurotrophic factor and dibutyryl cyclic AMP were not additive. Dibutyryl cyclic AMP injection into the dorsal root ganglion induced mRNAs for two other neuropoietic cytokines, interleukin-6 and leukemia inhibitory factor and increased the accumulation of phosphorylated STAT3 in neuronal nuclei. The in vitro conditioning action of dibutyryl cyclic AMP was partially blocked by a pharmacological inhibitor of Janus kinase 2, a neuropoietic cytokine signaling molecule. We suggest that the beneficial actions of increased cyclic AMP activity on axonal regeneration of primary sensory neurons are mediated, at least in part, through the induction of neuropoietic cytokine synthesis within the dorsal root ganglion.
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PMID:Actions of neuropoietic cytokines and cyclic AMP in regenerative conditioning of rat primary sensory neurons. 1711 14

Silibinin is a natural flavonoid antioxidant with anti-hepatotoxic properties and pleiotropic anticancer capabilities. We tested the hypothesis that silibinin inhibits cellular invasiveness by down-regulating the focal adhesion kinase (FAK) and extracellular signal-regulated protein kinase (ERK)-dependent c-Jun/activator protein-1 (AP-1) induction, which leads to inhibition of urokinase-type plasminogen activator (u-PA) and matrix metalloproteinase-2 (MMP-2) expressions in human osteosarcoma MG-63 cells. We found that silibinin decreased cell adhesion and invasiveness, as well as inhibited u-PA and MMP-2 expressions. Silibinin reduced ERK 1/2 phosphorylation, but had no effects on the phosphorylation of c-Jun N-terminal kinases (JNKs) 1/2, p38 and Akt. Silibinin suppressed AP-1-binding activity and c-Jun levels and its phosphorylation without changes of c-Fos and Ets-1 levels. Silibinin also inhibited interleukin-6-induced ERK 1/2 and c-Jun phosphorylation, and cell invasiveness. Thus, silibinin may possess an anti-metastatic activity in MG-63 cells.
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PMID:Silibinin suppresses human osteosarcoma MG-63 cell invasion by inhibiting the ERK-dependent c-Jun/AP-1 induction of MMP-2. 1711 26

Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposi's sarcoma, primary effusion lymphoma, and plasmablastic multicentric Castleman's disease. STAT3 has been shown to be important for the maintenance of primary effusion lymphoma cells in culture and is chronically activated in many tumor cell lines. However, little is known about the role of KSHV in the activation of STAT3 or the role of STAT3 in KS tumors. We demonstrate that STAT3 is activated by KSHV infection of endothelial cells, the KS tumor cell type, in a biphasic fashion. Viral binding and entry activate STAT3 in the first 2 h after infection, but this activation dissipates by 4 h postinfection. By 12 h after KSHV infection, concomitant with the expression of latent genes, STAT3 is once again activated, and this activation persists for as long as latent infection is maintained. Activated STAT3 translocates to the nucleus, where it can bind to STAT3-specific DNA elements and can activate STAT3-dependent promoter activity. Conditioned medium from KSHV-infected endothelial cells is able to transiently activate STAT3, indicating the involvement of a secreted factor and that a latency-associated factor in KSHV-infected cells is necessary for sustained activation. KSHV upregulates gp130 receptor expression, and both gp130 and JAK2 are required for the activation of STAT3. However, neither human nor viral interleukin-6 is required for STAT3 activation. Persistent activation of the oncogenic signal transducer, STAT3, by KSHV may play a critical role in the viral pathogenesis of Kaposi's sarcoma, as well as in primary effusion lymphomas.
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PMID:Persistent activation of STAT3 by latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells. 1715 Nov

In patients with chronic heart failure (CHF) increased plasma concentrations of proinflammatory cytokines are found. For example, the plasma interleukin-6 (IL-6) concentration correlates with disease severity. Beside IL-6 cardiotrophin-1 (CT-1), a member of the IL-6 superfamily, is also increased in CHF. We examined whether CT-1 is able to induce IL-6 in human umbilical vein endothelial cells (HUVEC) and characterised the underlying pathway. IL-6 mRNA was determined by real-time PCR and by RT-PCR in HUVEC which were stimulated with different CT-1 concentrations and for different time periods. IL-6 concentration in the supernatant was determined by ELISA. For the pathway determination following inhibitors were used: piceatannol (signal transducer and activation of transcription (STAT)3 phosphorylation), wortmannin (phosphatiylinositol 3-kinase (PI3K)), SB203580 (p38 mitogen-activated protein kinase (MAPK)), AG490 (Janus kinase (JAK)2), PD98059 (mitogen-activated protein kinase kinase (MEK) 1/2), parthenolide (nuclear factor kappaB) and cycloheximide (protein biosynthesis). CT-1 caused a concentration- and time-dependent increase in IL-6 mRNA in HUVEC with a maximal induction seen after 6 h (2-fold compared to control) with 100 ng/ml CT-1. In the supernatant of HUVEC a concentration- and time-dependent increase of IL-6 protein was found. A maximum effect with 100 ng/ml CT-1 was found after 24 h (11-fold compared to control). AG490, SB203580, piceatannol, parthenolide and cycloheximide inhibit CT-1 induced IL-6 mRNA and protein expression whereas wortmannin and PD98059 did not inhibit IL-6 expression. CT-1 induced both IL-6 mRNA and protein in a concentration- and time-dependent manner in HUVEC. The underlying pathway includes activation of JAK2, STAT3, p38 and NFkappaB. CT-1 induced IL-6 expression and requires protein synthesis and IL-6 is not stored intracellularly. We speculate that in CHF CT-1 might be in part responsible for increased IL-6 plasma concentrations. Modulation of the CT-1 pathway may be a further strategy in CHF treatment.
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PMID:Cardiotrophin-1 induces interleukin-6 synthesis in human umbilical vein endothelial cells. 1719 93

Oncostatin M (OSM) is a multifunctional cytokine of the interleukin-6 family and has been implicated in embryonic development, differentiation, inflammation, and regeneration of liver and bone. In the present study, we demonstrated that treatment of human adipose mesenchymal stem cells (hADSCs) with OSM-attenuated adipogenic differentiation, as indicated by decreased accumulation of intracellular lipid droplets and down-regulated expression of adipocytic markers, such as lipoprotein lipase and PPARgamma. However, OSM treatment stimulated osteogenic differentiation, as demonstrated by the increase in matrix mineralization and expression levels of osteogenic differentiation markers, including alkaline phosphatase, Runx2, and osteocalcin. OSM treatment induced activation of JAK2, JAK3, and ERK in hADSCs, and pre-treatment of hADSCs with the JAK2 inhibitor, AG490, significantly restored the OSM-induced inhibition of adipogenic differentiation. Whereas, the JAK3 inhibitor, WHI-P131, and the MEK inhibitor, U0126, had no effects on the anti-adipogenic activity of OSM. On the other hand, the pro-osteogenic activity of OSM was prevented by treatment of the cells with WHI-P131 or U0126, but not with AG490. These results indicate that distinct signaling pathways, including JAK2, JAK3, and MEK-ERK, play specific roles in the OSM-induced anti-adipogenic and pro-osteogenic differentiation of hADSCs.
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PMID:Oncostatin M promotes osteogenesis and suppresses adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells. 1722 68

Lipoteichoic acid (LTA) is a cell surface glycoconjugate of gram-positive bacteria and is reported to activate the innate immune system. We previously reported that purified LTA obtained from Enterococcus hirae has no immunostimulating activity, but a subfraction (Eh-AF) in an LTA fraction possesses activity. In this study, we established a mouse monoclonal antibody neutralizing the activity of Eh-AF and investigated its inhibitory effects. Monoclonal antibody (MAbEh1) was established by the immunization of BALB/c mice with Eh-AF, followed by hybridoma screening based on its inhibitory effect for the production of interleukin-6 (IL-6) induced by Eh-AF. MAbEh1 neutralized the production of IL-6 by LTA fraction from not only E. hirae but also Staphylococcus aureus, while it failed to block that of lipopolysaccharide, suggesting that the antibody recognized a common active structure(s) in LTA fractions. Synthetic glycolipids in these LTAs did not induce cytokine production, at least in our system. Interestingly, the antibody was found to inhibit the activity of immunostimulating synthetic lipopeptides, Pam(3)CSK(4) and FSL-1. These results suggest that MAbEh1 neutralizes the activity of lipoprotein-like compounds which is responsible for the activity of the LTA fraction of E. hirae and S. aureus.
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PMID:Evidence of immunostimulating lipoprotein existing in the natural lipoteichoic acid fraction. 1728 98

Pioglitazone is widely used for the treatment of diabetic patients with insulin resistance. The mechanism of pioglitazone to improve insulin sensitivity is not fully understood. Recent studies have shown that the induction of suppressor of cytokine signaling 3 (SOCS3) is related to the development of insulin resistance. Here, we examined whether the insulin-sensitizing effect of pioglitazone affects the SOCS induction. In db/db mice and high-fat-fed mice, expression of SOCS3 mRNA in fat tissue was increased compared with that in lean control mice, and pioglitazone suppressed SOCS3 levels. In 3T3-L1 adipocytes, mediators of insulin resistance such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6, growth hormone, and insulin increased SOCS3 expression, which was partially inhibited by pioglitazone. The ability of pioglitazone to suppress SOCS3 induction by TNF-alpha was greatly augmented by peroxisome proliferator-activated receptor gamma overexpression. SOCS3 overexpression and tyrphostin AG490, a Janus kinase 2 inhibitor, or dominant-negative STAT3 expression partially inhibited adiponectin secretion and was accompanied by decreased STAT3 phosphorylation. Conversely, pioglitazone increased adiponectin secretion and STAT3 phosphorylation in fat tissue of db/db mice and in 3T3-L1 adipocytes. These results suggest that pioglitazone exerts its effect to improve whole-body insulin sensitivity in part through the suppression of SOCS3, which is associated with the increase in STAT3 phosphorylation and adiponectin production in fat tissue.
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PMID:Effects of pioglitazone on suppressor of cytokine signaling 3 expression: potential mechanisms for its effects on insulin sensitivity and adiponectin expression. 1732 50


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