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)

To characterize the biological activity of tocilizumab, a humanized anti-human interleukin-6 receptor (IL-6R) monoclonal antibody, we examined its binding activity to both soluble IL-6R (sIL-6R) and membrane bound IL-6R (mIL-6R) and its neutralizing activity to other IL-6 family cytokines. ELISA assay demonstrated that tocilizumab bound to sIL-6R and inhibited IL-6 binding to sIL-6R in a dose-dependent manner. The dissociation constant (Kd value) for IL-6R was determined to be 2.54+/-0.12 nmol/L by Scatchard analysis. In addition, tocilizumab had the ability to dissociate IL-6 and sIL-6R from their preformed complex. The immune complex of tocilizumab and sIL-6R did not transmit signaling. Moreover, tocilizumab suppressed the IL-6/sIL-6R complex-induced proliferation of human gp130-transfected cell, BAF-h130. In addition, tocilizumab had the ability to bind to human IL-6R expressing COS-7 cells and to suppress the growth of the IL-6-dependent myeloma cell line, KPMM2. Finally, to analyze the specificity of this antibody, the effects on signal transduction of IL-6 family cytokines such as interleukin-11 (IL-11), oncostatin M (OSM), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF) were examined using murine transfectant cell lines (BaF/IL-6R, BaF/IL-11R, BaF/OSMR, BaF/LIFR and BaF/CNTFR) that proliferate depending on IL-6, IL-11, OSM, LIF and human CNTF, respectively. Tocilizumab inhibited the proliferation of BaF/IL-6R induced by IL-6, but did not inhibit the proliferation of BaF/IL-11R, BaF/OSMR, BaF/LIFR and BaF/CNTFR cells induced by their corresponding cytokines. These lines of evidence indicate that tocilizumab is able to bind to both sIL-6R and mIL-6R and to inhibit IL-6 binding to its receptors, leading to the blockade of the IL-6 signaling through both sIL-6R and mIL-6R, but not block the signaling of other IL-6 family cytokines.
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PMID:Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. 1610 23

The cytokine receptor gp130 is the shared signalling subunit of the IL-6-type cytokines. Interleukin-6 (IL-6) signals through gp130 homodimers whereas leukaemia inhibitory factor (LIF) exerts its action through a heterodimer of gp130 and the LIF receptor (LIFR). Related haematopoietic receptors such as the erythropoietin receptor have been described as preformed dimers in the plasma membrane. Here we investigated gp130 homodimerization and heterodimerization with the LIFR by fluorescence resonance energy transfer (FRET) and bimolecular fluorescence complementation (BiFC). We detected a FRET signal between YFP- and CFP-tagged gp130 at the plasma membrane of unstimulated cells that does not increase upon IL-6 stimulation. However, FRET between YFP-tagged gp130 and CFP-tagged LIFR considerably increased upon LIF stimulation. Using a BiFC approach that detects stable interactions we show that fluorescence complementation of gp130 constructs tagged with matching 'halves' of fluorescent proteins increases upon IL-6 stimulation. Taken together, these findings suggest that transient gp130 homodimers on the plasma membrane are stabilized by IL-6 whereas heterodimerization of gp130 with the LIFR is mainly triggered by the ligand. This view is supported by the observation that the simultaneous action of two IL-6 binding domains on two gp130 molecules is required to efficiently recruit a fluorescent IL-6 (YFP-IL-6) to the plasma membrane.
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PMID:Dimerization of the cytokine receptors gp130 and LIFR analysed in single cells. 1625 48

Cytokines play a central role in maintaining self-renewal in mouse embryonic stem (ES) cells through a member of the interleukin-6 type cytokine family termed leukemia inhibitory factor (LIF). LIF activates the JAK-STAT3 pathway through the class I cytokine receptor gp130, which forms a trimeric complex with LIF and the class I cytokine receptor LIF receptor beta. STAT3 has been shown to play a crucial role in self-renewal in mouse ES cells probably by induction of c-myc expression. Thus, ablation of STAT3 activation leads to differentiation. However, important connections between STAT3 and other signalling pathways have been documented. In addition, gp130 activation leads to both PI3K and Src activation. The canonical Wnt pathway is sufficient to maintain self-renewal of both human ES cells and mouse ES cells. It seems quite possible that the main pathway maintaining self-renewal in ES cells is the Wnt pathway, while the LIF-JAK-STAT3 pathway is present in mouse cells as an adaptation for sustaining self-renewal during embryonic diapause, a condition of delayed implantation in mammals. In keeping with this scenario, the Wnt pathway has been shown to elevate the level of c-myc. Thus, the two pathways seem to converge on c-myc as a common target to promote self-renewal. Whereas LIF does not seem to stimulate self-renewal in human embryonic stem cells it cannot be excluded that other cytokines are involved. The pleiotropic actions of the increasing number of cytokines and receptors signalling via JAKs, STATs and SOCS exhibit considerable redundancy, compensation and plasticity in stem cells in accordance with the view that stem cells are governed by quantitative variations in strength and duration of signalling events known from other cell types rather than qualitatively different stem cell-specific factors.
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PMID:Cytokine signalling in embryonic stem cells. 1648 Apr 48

Leukemia inhibitory factor (LIF) and oncostatin M (OSM) are found in appreciable concentrations in synovial fluid from patients with rheumatoid arthritis (RA) but not osteoarthritis. Accordingly, both are potential therapeutic targets in inflammatory diseases of the joints. Several LIF antagonists have been developed. They have the capacity to inhibit the biologic activities of not only LIF but also other interleukin-6 (IL-6) subfamily cytokines, including OSM. Both LIF and OSM share the same receptor, which is part of a cytokine receptor super family in which the glycoprotein 130 (gp130) subunit is a common constituent. The aim of this study was to evaluate the antagonistic potentials of two LIF mutants, LIF05 and MH35-BD. Both are mutant forms of human LIF with reduced affinity for gp130 and greater LIF receptor (LIFR) binding affinity. The results, using Ba/F3 cell proliferation assay, acute-phase protein (haptoglobin) induction analysis in HepG2 human hepatoma cells, a porcine cartilage glycosaminoglycan release assessment for proteoglycan degradation, and a collagen release assay, show that these antagonists inhibit relevant LIF, OSM, and other IL-6 subfamily cytokines in vitro albeit with differential potencies and have, therefore, therapeutic potential for treatment of RA and perhaps other diseases.
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PMID:In vitro evaluation of leukemia inhibitory factor receptor antagonists as candidate therapeutics for inflammatory arthritis. 1747 16

Plasminogen activator inhibitor-1 (PAI-1) plays a pivotal role in the regulation of the fibrinolytic system and in the modulation of extracellular proteolysis. Increased PAI-1 was found in atherosclerotic lesions, and high PAI-1 plasma levels were associated with coronary heart disease. Smooth muscle cells (SMC) are a major source of PAI-1 within the vascular wall, and PAI-1 was implicated in SMC migration, proliferation, and apoptosis. We treated human coronary artery SMC (HCASMC) and human aortic SMC (HASMC) with the glycoprotein 130 (gp130) ligands cardiotrophin-1, interleukin-6 (IL-6), leukemia inhibitory factor (LIF), or oncostatin M (OSM). Only OSM increased PAI-1 antigen and activity production significantly in these cells up to 20-fold. OSM upregulated mRNA specific for PAI-1 up to 4.5-fold in these cells. HCASMC and HASMC express gp130, OSM receptor, IL-6 receptor, and LIF receptor. OSM induced extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylations in HASMC. A phosphatidylinositol 3-kinase inhibitor and a mitogen-activated protein/extracellular signal-regulated kinase inhibitor reduced Akt and ERK1/2 phosphorylation, respectively, and abolished OSM-induced PAI-1 upregulation. A janus kinase/signal transducer and activator of transcription inhibitor, a p38 mitogen-activated protein kinase inhibitor, or c-Jun NH(2)-terminal kinase inhibitor I did not inhibit the OSM-dependent PAI-1 induction. OSM enhanced proliferation of both HCASMC and HASMC by 77 and 90%, respectively. We hypothesize that, if the effect of OSM on PAI-1 expression in smooth muscle cells is operative in vivo, it could, via modulation of fibrinolysis and extracellular proteolysis, be involved in the development of vascular pathologies such as plaque progression, destabilization and subsequent thrombus formation, and restenosis and neointima formation.
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PMID:The inflammatory cytokine oncostatin M induces PAI-1 in human vascular smooth muscle cells in vitro via PI 3-kinase and ERK1/2-dependent pathways. 1760 27

Leukemia inhibitory factor (LIF) is a member of the interleukin-6 family of cytokines and signals through the glycoprotein 130 and LIF receptor beta subunits. Binding of cytokines to these subunits activates multiple signaling cascades, including the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) pathway. We used compartmentalized cultures of sympathetic neurons and immunocytochemical analyses of STAT3 to examine the mechanisms involved in retrograde signaling of LIF from distal neurites (DN) to cell bodies. Addition of LIF to the DN of these neurons triggers the activation and nuclear translocation of STAT3. Inhibition of Jak activity in the cell bodies prevented LIF-induced retrograde activation of STAT3, while block of Jak activity in the DN had no effect on the appearance of activated STAT3 in the nucleus. These results show that the transport of activated Jak is not the main mechanism mediating retrograde signaling. Although there is an increase in phosphorylated STAT3 in the neurites after distal stimulation, the transport of activated STAT3 is not necessary for retrograde signaling. Our results are consistent with a signaling endosome model for retrograde signaling, in which the LIF/glycoprotein 130/LIF receptor/Jak complex is internalized and transported to activate STAT3 in the cell body.
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PMID:Retrograde activation of STAT3 by leukemia inhibitory factor in sympathetic neurons. 1760 45

How diverse stimuli control hemopoietic lineage development is unknown. An early event during induction of macrophage differentiation in the myeloblastic leukemia M1 cell line by different stimuli, such as leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), is expression of the colony-stimulating factor-1 receptor (CSF-1R). We report that expression of active CSF-1R in M1 cells accelerated their subsequent terminal differentiation into macrophages in response to LIF and IL-6 when compared with cells lacking the CSF-1R or expressing the receptor with compromised kinase activity; however, there was no requirement for signaling through the CSF-1R, for example, via endogenous CSF-1, during the actual LIF-induced and IL-6-induced differentiation stage. Differences were noted in the signaling pathways downstream of the LIF receptor depending on the presence of the CSF-1R. Both LIF and IL-6 gave an additive response with CSF-1, consistent with LIF and IL-6 acting via a different signaling pathway (signal transducer and activator of transcription 3 dependent) than CSF-1 (extracellular signal-regulated kinase dependent). Based at least on this cell model, we propose that terminal macrophage differentiation involves a critical priming or deterministic phase in which signaling by the CSF-1R prepares a precursor population for subsequent rapid terminal macrophage differentiation by diverse stimuli. We also propose that expression and activation of the CSF-1R explain much prior literature on macrophage lineage commitment in M1 leukemic cells and may be important in controlling the progression of certain myeloid leukemias.
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PMID:The critical role of the colony-stimulating factor-1 receptor in the differentiation of myeloblastic leukemia cells. 1833 52

Oncostatin M (OSM) and leukemia inhibitory factor (LIF) belong to the interleukin-6 family of cytokines. The authors' previous in vitro work demonstrated that in mouse cells mouse OSM (mOSM) signals through a heterodimeric receptor complex incorporating the mOSM-specific receptor mOSMRbeta while human OSM (hOSM) and bovine OSM (bOSM) use the mouse LIF receptor mLIFRbeta rather than mOSMRbeta. These in vitro data suggest that prior studies in mouse systems with hOSM or bOSM (the usual molecules used in early studies) reflect LIF rather than OSM biology. The current work assessed whether or not this divergence in actions among these three OSMs also occurs in vivo in mouse models. Adult female (C57BL/6J x DBA/2J) F(1) mice were engineered to stably overexpress mOSM, hOSM, or bOSM by retrovirus-mediated gene transfer (n = 10 or more per group). After 4 weeks, molecular and hematologic profiles and anatomic phenotypes in multiple organs were assessed by standard techniques. Animals overexpressing either hOSM or bOSM had an identical phenotype resembling that associated with LIF activation, including significant hematologic abnormalities (anemia, neutrophilia, lymphopenia, eosinopenia, and thrombocytosis); weight loss; profound enlargement (lymph node, spleen) and/or structural reorganization (lymph node, spleen, thymus) of lymphoid organs; and severe osteosclerosis. In contrast, mice overexpressing mOSM did not develop hematologic changes, weight loss, or osteosclerosis and exhibited more modest and anatomically distinct restructuring of lymphoid organs. These data indicate that activities imputed to OSM and the mOSMRbeta signaling pathway using in vitro and in vivo mouse experimental systems are unique to mOSM.
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PMID:Mice overexpressing murine oncostatin M (OSM) exhibit changes in hematopoietic and other organs that are distinct from those of mice overexpressing human OSM or bovine OSM. 1911 26

Leukemia inhibitory factor (LIF) is a soluble interleukin-6 family cytokine that regulates a number of physiologic functions, including normal skeletal remodeling. LIF signals through the cytokine co-receptor glycoprotein-130 in complex with its cytokine-specific receptor [LIF receptor (LIFR)] to activate signaling cascades in cells of the skeletal system, including stromal cells, chondrocytes, osteoblasts, osteocytes, adipocytes, and synovial fibroblasts. LIF action on skeletal cells is cell-type specific, and frequently dependent on the state of cell differentiation. This review describes the expression patterns of LIF and LIFR in bone, their regulation by physiological and inflammatory agents, as well as cell-specific influences of LIF on osteoblast, osteoclast, chondrocyte, and adipocyte differentiation. The actions of LIF in normal skeletal growth and maintenance, in pathological states (e.g. autocrine tumor cell signaling and growth in bone) and inflammatory conditions (e.g. arthritis) will be discussed, as well as the signaling pathways activated by LIF and their importance in bone formation and resorption.
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PMID:Leukemia inhibitory factor: a paracrine mediator of bone metabolism. 2230 8

Cytokines, which are generally involved in the process of inflammation, may also play a critical role in conceptus implantation. We examined: (1) the expression profiles of leukemia inhibitory factor (LIF) and interleukin (IL)-6 mRNA and their protein content in the endometrium of cyclic and pregnant gilts on Days 10 to 18 after estrus; (2) the effect of conceptus-exposed medium on LIF and IL-6 synthesis in the endometrium; (3) the profiles of IL6R and LIFR mRNA expression in pig conceptuses collected on Days 10 to 18 of pregnancy; and (4) the effect of LIF and IL-6 on the attachment and proliferation of porcine trophoblast cells. The expression of LIF mRNA in the endometrium increased between Days 10 and 12 in both cyclic and pregnant gilts, and tended to be higher in Day 12 pregnant animals compared with nonpregnant ones. The LIF protein content in the uterine lumen peaked on Day 12 of pregnancy, and was higher than on Day 12 of the estrous cycle. Endometrial IL-6 mRNA expression was upregulated on Day 12 in pregnant gilts compared with nonpregnant animals. Moreover, a higher content of IL-6 protein was observed in pregnant than in cyclic gilts. The addition of conceptus-exposed medium resulted in up-regulation of LIF and IL6 mRNA expression, and increased IL-6 content in endometrial slices. In conceptuses, increased mRNA expression was detected on Days 10 to 14 for IL6R and on Day 14 for LIFR, when compared with other days studied. LIF and IL-6 stimulated the attachment and proliferation of trophoblast cells in vitro. In summary, LIF and IL-6 are important components of embryo-uterine interactions during early pregnancy in the pig, and may contribute to successful conceptus implantation.
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PMID:Regulation of expression and role of leukemia inhibitory factor and interleukin-6 in the uterus of early pregnant pigs. 2292 May 93


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