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)

Serum concentrations of interleukin-6 (IL-6), IL-6-soluble receptor (sIL-6R), IL-6 gp130-soluble receptor (sgp130), ligand of receptor activator of nuclear factor (NF)-kappaB (RANKL), and osteoprotegerin (OPG) were determined in 42 patients with polyostotic Paget's disease of bone (PDB) and acquired resistance to clodronate (M/F ratio 23:19; mean age 58.5 +/- 9.4 years) in acute phase of disease and after oral risedronate treatment (30 mg/day for 8 weeks). At baseline, pagetic patients showed higher levels of OPG, sIL-6R, and IL-6 with lower levels of sgp130 compared to 24 age- and sex-matched controls (respectively, 4.69 +/- 1.27 vs. 2.87 +/- 0.54 pmol/L; 40.89 +/- 8.61 vs. 30.98 +/- 4.24 ng/ml; 3.59 +/- 0.97 vs. 1.8 +/- 0.9 pg/ml; 327.34 +/- 43.41 vs. 411.7 +/- 79.5 ng/ml). Response to treatment is related to a significant increase of OPG levels in all patients (from 4.69 +/- 1.27 to 5.48 +/- 1.31 pmol/L). The disease remission, that is, total alkaline phosphatase (tALP) levels within the normal range after therapy, was associated with a simultaneous increase in OPG and sgp130 levels. In patients with tALP higher than the normal range after therapy, the OPG increase was associated with a parallel increase in RANKL levels. Our data suggest that serum levels of components of RANKL/OPG and IL-6 systems, before and after treatment, may be used to better define a therapeutical strategy in pagetic patients.
 ...
PMID:Interleukin-6 and osteoprotegerin systems in Paget's disease of bone: relationship to risedronate treatment. 1577 35

The pro-inflammatory cytokine interleukin-6 (IL-6) together with its soluble receptor (sIL-6R) induces and maintains thermal hyperalgesia. It facilitates the heat-induced release of calcitonin gene-related peptide from rat cutaneous nociceptors in vivo and in vitro. Here we report that exposure of nociceptive neurons to the IL-6-sIL-6R complex or the gp130-stimulating designer IL-6-sIL-6R fusion protein Hyper-IL-6 (HIL-6) resulted in a potentiation of heat-activated inward currents (I(heat)) and a shift of activation thresholds towards lower temperatures without affecting intracellular calcium levels. The Janus tyrosine kinase inhibitor AG490, the selective protein kinase C (PKC) inhibitor, bisindolylmaleimide 1 (BIM1), as well as rottlerin, a selective blocker of the PKCdelta isoform, but not the cyclooxygenase inhibitor indomethacin, effectively reduced the effect. Reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization revealed expression of mRNA for the signal-transducing beta subunit of the receptor gp130 in neuronal somata, rather than satellite cells in rat dorsal root ganglia. Together, the results suggest that IL-6-sIL-6R acts directly on sensory neurons. It increases their susceptibility to noxious heat via the gp130/Jak/PKCdelta signalling pathway.
 ...
PMID:Fast modulation of heat-activated ionic current by proinflammatory interleukin 6 in rat sensory neurons. 1581 18

Interleukin-6 (IL-6) plays a central role in the pathogenesis of several autoimmune and inflammatory diseases as well as B-cell lymphoproliferative disorders. This work describes the effects of the recombinant or adenovirally-delivered IL-6 superantagonist Sant7, anti-IL-6 and IL-6 receptor monoclonal antibodies in a severe murine model of human B-cell lymphoma induced in SCID mice by transplantation of an LCL-41 cell line variant (isotype-switched IgM>IgG). Survival of 60% of the animals treated with anti-gp130 was observed up to day 33, while about 20% of the animals survived with anti-gp80 and Sant7 treatment. No survival was observed with the anti-IL-6 monoclonal antibody treatment. No significant change in serum and peritoneal levels of human IL-6 (hIL-6) and soluble human IL-6 receptor (shIL-6R) was observed in the recombinant Sant7-treated group towards the control group. The anti-gp80 monoclonal antibody induced significant increase of both hIL-6R and hIL-6 in serum and peritoneum. The anti-gp130 monoclonal antibody treatment determined a reduction of the seric shIL-6R and a significant increase of the seric hIL-6. Anti-IL-6 monoclonal antibody administration resulted in a reduction of serum and in an increase of peritoneal hIL-6. Treatment with adenoviral Sant7 was associated with a reduction of circulating shIL-6R, hIgG and mSAP. However, only marginal anti-tumor efficacy of the adenoviral Sant7 was observed. Overall, the present data suggest a potential for anti-hIL-6 therapy in B-cell lymphomas. Less severe animal models might be useful to better evaluate Sant7 efficacy alone or in combination with other anti-IL-6 therapeutics.
 ...
PMID:Comparative activity of Sant7 and anti-IL-6, IL-6R monoclonal antibodies in a murine model of B-cell lymphoma. 1606 91

Cardiac surgery with cardiopulmonary bypass (CPB) elicits an inflammatory response and has a multitude of biological consequences, ranging from subclinical organ dysfunction to severe multiorgan failure. Pediatric patients are more prone to have a reaction that can jeopardize their outcome. Cytokines are supposed to be important mediators in this response: limiting their circulating levels is, therefore, appealing. We investigated the pattern of cytokine release during pediatric operation for congenital heart anomalies in 20 patients, and the effect of hemofiltration. Tumor necrosis factor alpha (TNF-alpha) was elevated after anesthesia induction and showed significant decrease during CPB. Hemofiltration reduced its concentration, but the effect disappeared on the following day. Interleukin-1 (IL-1) increased slowly at the end of CPB and hemofiltration had no effect. Interleukin-6 (IL-6) showed a tendency toward augmentation during rewarming and hemofiltration did not significantly affect the course. Soluble interleukin-6 receptor (sIL-6r) had a pattern similar to TNF-alpha, but hemofiltration had no effect. On the other hand, interleukin-8 (IL-8) behaved like IL-6. Our findings suggest that baseline clinical status, anesthetic drugs, and maneuvers before incision may elicit a cytokine response, whereas rewarming is a critical phase of CPB. Hemofiltration is effective in removal of TNF-alpha, but its role is debatable for the control of IL-1, IL-6, sIL-6r and IL-8 levels.
 ...
PMID:Inflammatory cytokines in pediatric cardiac surgery and variable effect of the hemofiltration process. 1623 22

Interleukin-6-type cytokine receptors are expressed in polarized cells such as hepatocytes and intestinal cells. For the interleukin-6-receptor gp80 and its signal transducer gp130, a preferential basolateral localization was demonstrated in Madin-Darby canine kidney (MDCK) cells and two basolateral sorting signals were identified within the cytoplasmic domain of gp80. The cytoplasmic tail of gp130 is responsible for signaling via the Janus kinase/signal transducer and activator of transcription pathway. In addition, it mediates the internalization of the receptor complex which is dependent on a di-leucine motif. Truncated gp130 lacking the cytoplasmic domain is sorted apically in MDCK cells. For identification of the basolateral sorting signal(s) of gp130, a series of deletion mutants in the cytoplasmic domain of gp130 have been generated and stably expressed in MDCK cells. Biotinylation analyses of these mutants show that a ten amino acids sequence between amino acids 782 and 792 which contains the di-leucine internalization motif is also essential for a basolateral sorting. Accordingly, we detect apical delivery of a gp130 mutant in which the di-leucine motif has been exchanged by two alanines (gp130LL/AA). These findings indicate that the di-leucine motif which directs the internalization of the IL-6 receptor complex also mediates the basolateral sorting of the signal transducer gp130.
 ...
PMID:Identification of a basolateral sorting signal within the cytoplasmic domain of the interleukin-6 signal transducer gp130. 1627 60

Interleukin-6 (IL-6) and its soluble receptor (sIL-6R) are major factors for maintenance and expansion of hematopoietic stem cells (HSCs). Sensitivity of HSCs to IL-6 has been previously studied, in part by measuring the expression of IL-6R on the membrane (mIL-6R). Several studies have described the regulation of cell surface expression of IL-6R by several cytokines, but the role of glycoprotein 130 activation has not yet been investigated. In this study, CD133(+) cells were purified from adult peripheral blood and were precultured in the absence or presence of 5-fluorouracil (5-FU) for selection of quiescent HSCs. Cells were cultured with continuous or pulsed stimulations of an IL-6-sIL-6R fusion protein (hyperinterleukin-6 [HIL-6]) to 1) detect mIL-6R by flow cytometry, 2) assess mIL-6R and sIL-6R RNAs by reverse transcription-polymerase chain reaction, 3) measure sIL-6R in supernatants by enzyme-linked immunosorbent assay, 4) analyze cell-cycle status, and 5) perform long-term culture-initiating cell assays. The level of mIL-6R(-) cells was preserved by 5-FU incubation. HIL-6 increased steady-state mIL-6R RNA and expression rate on HSCs, independently of treatment with 5-FU. Enhanced production of sIL-6R was observed with short pulses of HIL-6 on CD133(+) 5-FU-pretreated cells. This overproduction of sIL-6R was abrogated by tumor necrosis factor-alpha protease inhibitor-1, an inhibitor of a disintegrin and metalloprotease proteases, suggesting the shedding of mIL-6R. This phenomenon was mediated through the phosphatidylinositol-3'-kinase pathway and was involved in the maintenance of primitive HSCs. In conclusion, expression and production of IL-6R are tightly regulated and stage specific. We assume that sIL-6R produced by shedding should be involved in autocrine and paracrine loops in the HSC microenvironment.
 ...
PMID:Multilevel regulation of IL-6R by IL-6-sIL-6R fusion protein according to the primitiveness of peripheral blood-derived CD133+ cells. 1635 44

Autocrine growth factor stimulation resulting in growth self-sufficiency is a hallmark of cancer. Classically, non-small-cell lung cancer (NSCLC) cells have autocrine epidermal growth factor stimulation through coexpression of receptors and ligands. In addition to epidermal growth factor receptor and other growth factor ligand-receptor autocrine loops, increasing evidence suggests important roles for cytokines in mediating intracellular signaling events important in cell growth and survival. Interleukin-6 (IL-6) has been shown to activate pathways important in tumorigenesis including Janus kinase/signal transducer and activator of transcription, phosphotidylinositol 3-kinase/Akt, and extracellular signal-regulated kinase signaling. Using immunohistochemistry, we demonstrate that NSCLC specimens have tumor expression of IL-6 and IL-6 receptor components gp80 and gp130. These results suggest that IL-6 autocrine signaling might contribute to downstream signaling events in NSCLC and further support the concept of multiple autocrine pathways contributing to the pathogenesis of NSCLC.
 ...
PMID:Autocrine interleukin-6/interleukin-6 receptor stimulation in non-small-cell lung cancer. 1651 82

Interleukin-6 (IL-6) is an important cytokine in liver regeneration, and elevated levels of IL-6 have been demonstrated in patients with chronic liver diseases (CLD). Many biological effects of IL-6 depend on naturally occurring soluble IL-6 receptors. In the present study we measured the concentrations of IL-6 and its soluble receptors in the sera of patients with CLD related to hepatitis C virus (HCV) infection. We studied 77 patients with varying degrees of HCV-related CLD. Serum levels of IL-6 and its soluble receptors (sIL-6R, sgp130) were measured by enzyme-linked immunosorbent assay. Serum IL-6 and sIL-6R were elevated in patients with CLD compared with healthy subjects. Serum levels of sgp130 did not differ between patients with chronic hepatitis and healthy subjects. However, in patients with liver cirrhosis, sgp130 was significantly elevated and was positively correlated with total bilirubin and negatively correlated with cholinesterase and prothrombin time. Our study demonstrated that in patients with HCV-related CLD, serum IL-6 and its soluble receptor levels are correlated with both liver function impairment and the degree of liver fibrosis. These observations suggest that the balance of IL-6 and its soluble receptors may correspond to the state of liver damage in patients with CLD.
 ...
PMID:Serum levels of interleukin-6 and its soluble receptors in patients with hepatitis C virus infection. 1669 22

In murine models of Crohn's disease, rheumatoid arthritis and colon cancer, IL-6 (interleukin-6) signalling via the sIL-6R (soluble IL-6 receptor; termed IL-6 trans-signalling) has been shown to promote the pathology associated with these conditions. These detrimental activities can, however, be selectively blocked by soluble forms of the gp130 (glycoprotein 130) receptor. Although sgp130 (soluble gp130) therefore represents a viable therapeutic modality for the treatment of these conditions, the mass manufacture of such biologics is often expensive. The advent of molecular farming has, however, provided an extremely cost-effective strategy for the engineering of recombinant proteins. Here, we describe the expression and production of a biologically active sgp130 variant that is expressed in transgenic tobacco plants as an ELP (elastin-like peptide)-fusion protein (mini-gp130-ELP). Mini-gp130-ELP consists of the first three domains of gp130 (Ig-like domain and cytokine binding module) fused to 100 repeats of ELP. Expression of mini-gp130-ELP did not affect the growth rate or morphology of the transgenic plants, and purification was achieved using inverse transition cycling. This approach led to an overall yield of 141 microg of purified protein per g of fresh leaf weight. The purified mini-gp130-ELP specifically inhibited sIL-6R-mediated trans-signalling as measured by binding to the IL-6-sIL-6R complex and through its ability to block sIL-6R-mediated activation of STAT3 (signal transducer and activator of transcription 3) phosphorylation and proliferation in human hepatoma cells and murine pre-B-cells. Consequently, the present study validates the potential application of molecular farming in transgenic tobacco plants as a strategy for the expression and purification of therapeutically advantageous biologics such as sgp130.
 ...
PMID:Functional expression of a biologically active fragment of soluble gp130 as an ELP-fusion protein in transgenic plants: purification via inverse transition cycling. 1671 47

Influenza virus infection during pregnancy has been implicated as one of cause of premature delivery, abortion and stillbirth. We have reported that cultured human fetal membrane chorion cells undergoing apoptosis by influenza virus infection secrete unidentified heat-stable monocyte differentiation-inducing (MDI) factors. In this study, cellular, biological and immunochemical characteristics of MDI factors were investigated using human monocytic leukemia THP-1 cells by nitroblue tetrazolium reduction and cell adhesion assays. The treatment of THP-1 cells with culture supernatants from the influenza virus-infected chorion cells induced the nitroblue tetrazolium reduction ability, which was inhibited by the addition of superoxide dismutase and diphenyleneiodonium chloride, an inhibitor for reduced nicotinamide adenine dinucleotide phosphate oxidase. The phenomenon was also observed in human peripheral blood monocytes and histiocytic leukemia U937 cells, but not in promyelocytic leukemia HL-60 cells. The induction of nitroblue tetrazolium reduction and adhesion abilities in THP-1 cells was closely correlated with the concentrations of interleukin-6 protein in the culture supernatants. These abilities were inhibited to approximately 60% by the addition of antibodies against interleukin-6, or alpha-chain (gp80) or beta-chain (gp130) of IL-6 receptor. The induction of nitroblue tetrazolium reduction was increased by the addition of supernatants from amniochorion tissue cultures after influenza virus infection. These results indicate that chorion cell-derived interleukin-6 is partly responsible for monocyte differentiation to macrophages capable of generating superoxide anion. It is possible that these pathways represent part of the mechanism for birth complications associated with intrauterine influenza infection in pregnancy.
 ...
PMID:Characterization of monocyte differentiation-inducing (MDI) factors derived from human fetal membrane chorion cells undergoing apoptosis after influenza virus infection. 1682 80


<< Previous 1 2 3 4 5 6 7 8 9 10