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)

Caveolae, specialized flask-shaped lipid rafts on the cell surface, are composed of cholesterol, sphingolipids, and structural proteins termed caveolins; functionally, these plasma membrane microdomains have been implicated in signal transduction and transmembrane transport. In the present study, we examined the role of caveolin-1 in multiple myeloma cells. We show for the first time that caveolin-1, which is usually absent in blood cells, is expressed in multiple myeloma cells. Analysis of myeloma cell-derived plasma membrane fractions shows that caveolin-1 is co-localized with interleukin-6 receptor signal transducing chain gp130 and with insulin-like growth factor-I receptor. Cholesterol depletion by beta-cyclodextrin results in the loss of caveola structure in myeloma cells, as shown by transmission electron microscopy, and loss of caveolin-1 function. Interleukin-6 and insulin-like growth factor-I, growth and survival factors in multiple myeloma, induce caveolin-1 phosphorylation, which is abrogated by pre-treatment with beta-cyclodextrin. Importantly, inhibition of caveolin-1 phosphorylation blocks both interleukin-6-induced protein complex formation with caveolin-1 and downstream activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. beta-Cyclodextrin also blocks insulin-like growth factor-I-induced tyrosine phosphorylation of insulin-responsive substrate-1 and downstream activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. Therefore, cholesterol depletion by beta-cyclodextrin abrogates both interleukin-6- and insulin-like growth factor-I-triggered multiple myeloma cell survival via negative regulation of caveolin-1. Taken together, this study identifies caveolin-1 and other structural membrane components as potential new therapeutic targets in multiple myeloma.
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PMID:Essential role of caveolae in interleukin-6- and insulin-like growth factor I-triggered Akt-1-mediated survival of multiple myeloma cells. 1248 78

Essential amino acids, such as L-Arginine (Arg) and L-Lysine (Lys), are involved in bone metabolism and growth. Our previous studies analyzed the effect of these amino acids on rat osteoblast cultures and in experimental animals. In this study, we evaluated the effect of L-Arg and L-Lys on cultured human osteoblasts. Primary human osteoblast cultures were divided into four groups: the Arg Group received 0.625 mg/ml per day of Arg, the Lys Group 0.587 mg/ml per day of Lys, the Arg-Lys Group received both amino acids, whereas the Control Group was sham-treated. After 7 days, the following parameters were tested in all groups: alkaline phosphatase (ALP), nitric oxide (NO), calcium (Ca), phosphorus (P), osteocalcin (OC), type I collagen (PICP), interleukin-6 (IL-6), transforming growth factor-beta 1 (TGF-beta 1) on culture supernatant, platelet derived growth factor (PDGF), insulin-like growth factor-I (IGF-I), and MTT proliferation test on cells. Arg administration significantly increased ALP, NO, PICP and IGF-I production and reduced the level of IL-6. Lys administration over the same time interval mainly affected cell proliferation, as evidenced by the MTT test and immunostaining for PDGF. The same positive effects evidenced by the single administrations of the two amino acids resulted from their simultaneous administration. However, synergism could be demonstrated only for the decrease in the level of IL-6. Arg and Lys show a positive effect on human osteoblasts, which is related partly to the production of those factors required for matrix synthesis, and partly to the direct or mediated activation of cell proliferation.
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PMID:L-arginine and L-lysine stimulation on cultured human osteoblasts. 1250 70

Interleukin-6 (IL-6) is a growth and antiapoptotic factor for human myeloma cells. The autocrine loop and increased expression of the growth factor receptors have been postulated as the mechanisms of tumorigenesis. Here we show that IL-6 stimulation induced the phosphorylation of insulin-like growth factor-I (IGF-I) receptors in a human myeloma cell line, NOP2, highly expressing IL-6 receptor alpha (IL-6R alpha) and in the IL-6R alpha-transfected U266 cell line. IL-6-dependent complex formation of IL-6R alpha with IGF-I receptor beta was found in NOP2 where IL-6R alpha colocalized with IGF-I receptors at lipid rafts. Moreover, the IL-6-induced phosphorylation of IGF-I receptor beta was not blocked by a Janus kinase 2 (Jak2) inhibitor. In addition to the activation of the signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2, IL-6 stimulation led to the activation of Akt, presumably following the phosphorylation of IGF-I receptors. Thus, our results suggest that in NOP2, IL-6R alpha and IGF-I receptors exist on the plasma membrane in close proximity, facilitating the efficient assembly of 2 receptors in response to IL-6. The synergistic effects of highly expressed IL-6R alpha on IGF-I receptor-mediated signals provide a novel insight into the Jak-independent IL-6 signaling mechanism of receptor cross-talk in human myeloma cells.
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PMID:Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-I in myeloma cells that highly express IL-6 receptor alpha [corrected]. 1459 26

The androgen receptor co-activator CREB (cAMP-response element binding protein)-binding protein (CBP) enhances androgen receptor activity after stimulation by androgenic hormones and androgen receptor antagonists. The aim of the present study was to investigate the regulation of CBP expression by steroid and peptide hormones in prostate cancer. For this purpose, LNCaP cells were treated with the synthetic androgen methyltrienolone (R1881), epidermal growth factor, insulin-like growth factor-I or interleukin-6 (IL-6). CBP protein and mRNA expression were studied by western blotting and real-time PCR, respectively. CBP expression was also investigated in tissue specimens obtained from 26 patients with therapy-resistant carcinoma of the prostate. In LNCaP cells, CBP protein was down-regulated by R1881 or IL-6. The non-steroidal anti-androgen bicalutamide antagonized the effects of R1881 and the Janus kinase inhibitor AG 490 reversed the effects of IL-6. In contrast, neither R1881 nor IL-6 caused any effect on CBP expression in the PC-3 cell line. In LNCaP cells, the inhibition of CBP expression by R1881 or IL-6 was also observed at the mRNA level. CBP protein was detected in all 26 specimens by immunohistochemistry. The results suggest that up-regulation of CBP during androgen ablation may be relevant to the failure of endocrine therapy in patients with prostate carcinoma.
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PMID:The androgen receptor co-activator CBP is up-regulated following androgen withdrawal and is highly expressed in advanced prostate cancer. 1537 87

Aging is associated with decreased skeletal muscle mass and function. These changes are thought to derive, in part, from a reduction in skeletal muscle protein synthesis. Although some studies have shown reduced postabsorptive muscle protein synthesis with age in humans, recent studies have failed to find an age effect. In addition to this disparity, few studies have attempted to characterize the hormonal factors that may contribute to changes in protein synthesis. Thus we examined the effect of age on skeletal muscle protein metabolism, with a specific emphasis on myosin heavy chain (MHC) protein, and the relationship of protein synthesis rates to plasma hormone levels. We measured body composition, muscle function, muscle protein synthesis, MHC and actin protein content, MHC isoform distribution, and plasma concentrations of cytokines and insulin-like growth factor-I (IGF-I) in 7 young [29 +/- 2 (SE) yr] and 15 old (72 +/- 1 yr; P < 0.01) volunteers. Mixed-muscle (-19%; P = 0.11), MHC (-22%; P = 0.08), and nonmyofibrillar (-17%; P = 0.10) protein synthesis all tended to be lower in old volunteers. Old volunteers were characterized by increased circulating tumor necrosis factor-alpha receptor II (P < 0.05) and reduced IGF-I (P < 0.01). In addition, plasma C-reactive protein, interleukin-6, and tumor necrosis factor-alpha receptor II concentrations were negatively related to mixed-muscle and MHC protein synthesis rates (range of r values: -0.422 to -0.606; P < 0.05 to <0.01). No differences in MHC or actin protein content were found. Old volunteers showed reduced (P < 0.05) MHC IIx content compared with young volunteers but no differences in MHC I or IIa. Our data show strong trends toward reduced postabsorptive muscle protein synthesis with age. Moreover, reduced muscle protein synthesis rates were related to increased circulating concentrations of several markers of immune activation.
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PMID:Age-related differences in skeletal muscle protein synthesis: relation to markers of immune activation. 1561 83

Interactions between the cyclin-dependent kinase inhibitor flavopiridol and the small-molecule Bcl-2 antagonist HA14-1 were examined in human multiple myeloma cells. Whereas individual treatment of U266 myeloma cells with 10 micromol/L HA14-1 or 100 nmol/L flavopiridol had little effect, exposure of cells to flavopiridol (6 hours) followed by HA14-1 (18 hours) resulted in a striking increase in mitochondrial dysfunction (cytochrome c and Smac/DIABLO release; loss of mitochondrial membrane potential), activation of the caspase cascade, apoptosis, and diminished clonogenic survival. Similar findings were noted in other myeloma cell lines (e.g., MM.1S, RPMI8226, and NCI-H929) as well as in those resistant to dexamethasone and cytotoxic agents (e.g., MM.1R, 8226/Dox40, and 8226/LR5). Combined exposure to flavopiridol and HA14-1 was associated with down-regulation of Mcl-1 and Bcl-xL, Bid cleavage, and mitochondrial translocation of Bax. Flavopiridol/HA14-1-treated cells also exhibited a pronounced activation of Jun NH2-terminal kinase, a modest activation of p38 mitogen-activated protein kinase, and down-regulation of cyclin D1. Flavopiridol/HA14-1-induced apoptosis was associated with a marked increase in reactive oxygen species generation; moreover,both events were attenuated by the antioxidant N-acetyl-l-cysteine. Finally, in contrast to dexamethasone, flavopiridol/HA14-1-induced lethality was unaffected by exogenous interleukin-6 or insulin-like growth factor-I. Together, these findings indicate that flavopiridol and the small-molecule Bcl-2 antagonist HA14-1 cooperate to trigger oxidant injury, mitochondrial dysfunction, caspase activation, and apoptosis in human multiple myeloma cells and suggest that this approach may warrant further evaluation as an antimyeloma strategy.
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PMID:The small-molecule Bcl-2 inhibitor HA14-1 interacts synergistically with flavopiridol to induce mitochondrial injury and apoptosis in human myeloma cells through a free radical-dependent and Jun NH2-terminal kinase-dependent mechanism. 1563 44

The novel immunomodulator FTY720 down-modulates sphingosine-1-phosphate receptor 1 on lymphocytes at low nanomolar concentrations, thereby inhibiting sphingosine-1-phosphate receptor 1-dependent egress of lymphocytes from lymph nodes into efferent lymphatics and blood. At high micromolar concentration, FTY720 has been shown to induce growth inhibition and/or apoptosis in human cancer cells in vitro. In this study, we investigated the biological effects of FTY720 on multiple myeloma cells. We found that FTY720 induces potent cytotoxicity against drug-sensitive and drug-resistant multiple myeloma cell lines as well as freshly isolated tumor cells from multiple myeloma patients who do not respond to conventional agents. FTY720 triggers activation of caspase-8, -9, and -3, followed by poly(ADP-ribose) polymerase cleavage. Interestingly, FTY720 induces alterations in mitochondrial membrane potential (DeltaPsim) and Bax cleavage, followed by translocation of cytochrome c and Smac/Diablo from mitochondria to the cytosol. In combination treatment studies, both dexamethasone and anti-Fas antibodies augment anti-multiple myeloma activity induced by FTY720. Neither interleukin-6 nor insulin-like growth factor-I, which both induce multiple myeloma cell growth and abrogate dexamethasone-induced apoptosis, protect against FTY720-induced growth inhibition. Importantly, growth of multiple myeloma cells adherent to bone marrow stromal cells is also significantly inhibited by FTY720. Finally, it down-regulates interleukin-6-induced phosphorylation of Akt, signal transducers and activators of transcription 3, and p42/44 mitogen-activated protein kinase; insulin-like growth factor-I-triggered Akt phosphorylation; and tumor necrosis factor alpha-induced IkappaBalpha and nuclear factor-kappaB p65 phosphorylation. These results suggest that FTY720 overcomes drug resistance in multiple myeloma cells and provide the rationale for its clinical evaluation to improve patient outcome in multiple myeloma.
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PMID:FTY720 induces apoptosis in multiple myeloma cells and overcomes drug resistance. 1610 2

Tissue formation and repair are dependent upon cascades of biological events, but the signals involved and the possible gene coexpression patterns during intramembranous bone repair are only poorly understood. We sought to place this mode of regeneration in context by profiling quantitative gene expression for a panel of 39 genes between days 1 and 14 following rat femoral marrow ablation. In situ hybridization was employed to localize a subset of genes. Additionally, principal components analysis was conducted to identify underlying factors suggestive of coexpression patterns. During inflammation (days 1-5), several genes, including cyclooxygenase-1 and -2, showed downregulation. Other proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, exhibited increasing levels around day 5. During repair (days 3-10), growth factors, receptors, and inhibitor genes for transforming growth factor- beta; basic fibroblast growth factor; bone morphogenetic proteins 2, 4, and 7; vascular endothelial growth factor; and insulin-like growth factor-I were upregulated. In addition, the gene for core binding factor-alpha1 and markers of osteoblast function such as alkaline phosphatase, collagen type I, osteonectin, osteopontin, and osteocalcin had peak expression at day 5 or 7. The remodeling phase (days 10-14) was characterized by peaks for cytokines associated with osteoclastic activity including receptor activator of nuclear factor-kappaB, receptor activator of nuclear factor-kappaB ligand (RANKL), cathepsin K, tumor necrosis factor-alpha, interleukin-6, and cyclooxygenase-2. In situ hybridization showed that the most common sites of increased signal were within osteoblastic cells on trabecular and endosteal surfaces. Principal components analysis identified eight underlying factors that together explained over 80% of the variance in the data.
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PMID:Patterns and localization of gene expression during intramembranous bone regeneration in the rat femoral marrow ablation model. 1619 34

Bone marrow angiogenesis plays an important role in the pathogenesis and progression in multiple myeloma. Recent studies have shown that proteasome inhibitor bortezomib (Velcade, formerly PS-341) can overcome conventional drug resistance in vitro and in vivo; however, its antiangiogenic activity in the bone marrow milieu has not yet been defined. In the present study, we examined the effects of bortezomib on the angiogenic phenotype of multiple myeloma patient-derived endothelial cells (MMEC). At clinically achievable concentrations, bortezomib inhibited the proliferation of MMECs and human umbilical vein endothelial cells in a dose-dependent and time-dependent manner. In functional assays of angiogenesis, including chemotaxis, adhesion to fibronectin, capillary formation on Matrigel, and chick embryo chorioallantoic membrane assay, bortezomib induced a dose-dependent inhibition of angiogenesis. Importantly, binding of MM.1S cells to MMECs triggered multiple myeloma cell proliferation, which was also abrogated by bortezomib in a dose-dependent fashion. Bortezomib triggered a dose-dependent inhibition of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) secretion by the MMECs, and reverse transcriptase-PCR confirmed drug-related down-regulation of VEGF, IL-6, insulin-like growth factor-I, Angiopoietin 1 (Ang1), and Ang2 transcription. These data, therefore, delineate the mechanisms of the antiangiogenic effects of bortezomib on multiple myeloma cells in the bone marrow milieu.
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PMID:Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. 1639 31

Crohn's disease and ulcerative colitis are inflammatory diseases of the gastrointestinal tract characterized by chronic relapsing inflammation and catabolism. Growth hormone/insulin-like growth factor-I axis is important in inflammatory bowel disease, because of the effects on epithelial cell kinetics, collagen deposition and immunomodulation. The potential of growth hormone as a therapeutic option in inflammatory bowel disease has been proven in various clinical settings. Acquired growth hormone resistance in inflammatory bowel disease seems to be mediated by a combination of undernutrition and active inflammation. In particular, proinflammatory cytokines, such as TNF-a and interleukin-6, have been implicated as potential mediators of growth hormone resistance. The introduction of anti-TNF-alpha monoclonal antibodies has proven very efficacious in patients with inflammatory bowel disease. By reducing cytokines levels in inflammatory cells of intestinal mucosa, infliximab could interfere with cytokine-induced growth hormone resistance. Recent in vivo data have shown that acquired growth hormone resistance in patients with inflammatory bowel disease may be reversed after the administration of anti-TNF-alpha therapy.
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PMID:Growth hormone in inflammatory bowel disease. 1649 5


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