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)

The pathophysiology of the postpartum blues, common transient mood disorders in the first week postpartum, has remained elusive. Recently, however, it has been shown that depression and anxiety disorders are accompanied by activation of the inflammatory response system (IRS). This study was developed to determine whether the postnatal blues is associated with IRS activation. Serum concentrations of interleukin-6 (IL-6), IL-6 receptor (IL-6R), gp130 (the IL-6 signaling protein), IL-1R antagonist (IL-1RA) and leukemia inhibitory factor receptor (LIFR) were assayed in 22 nonpregnant women and in 91 pregnant women before delivery and 1 and 3 days after delivery. On each occasion the parturient women completed the State version of the Spielberger State-Trait-Anxiety-Inventory (STAI) and the Zung Depression Rating Scale (ZDS). Serum IL-6, IL-1RA and LIFR were significantly higher in pregnant women at the end of term than in nonpregnant women.
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PMID:Immune activation in the early puerperium is related to postpartum anxiety and depressive symptoms. 1067 77

Expression of glycoprotein 130 and the related receptors, including interleukin-6 receptor and leukemia inhibitory factor receptor, was examined in the murine cerebellum at the protein level. Western blot analysis revealed that interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 were expressed in the murine cerebellum. Immunoreactivities for interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 were strongly localized on the cell body of Purkinje cells, indicating that both interleukin-6 and leukemia inhibitory factor could act directly on Purkinje cells in murine adult mice. The expressions of interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 were observed on the cell membranes of Purkinje cells by immunoelectron microscopy. Immunoreactivity for the interleukin-6 receptor was also detected in the cytoplasm of Purkinje cells. Injection of a murine hemopoietic cell line, FDC-P1 cells, transfected with the complementary DNA encoding the leukemia inhibitory factor led to a reduction in calbindin-positive dendrites of the Purkinje cells.The present results suggest that the leukemia inhibitory factor affects cerebellar functions through Purkinje cells.
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PMID:Expression of interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 in the murine cerebellum and neuropathological effect of leukemia inhibitory factor on cerebellar Purkinje cells. 1103 18

To elucidate the function of the two cytokine-binding modules (CBM) of the leukemia inhibitory factor receptor (LIFR), receptor chimeras of LIFR and the interleukin-6 receptor (IL-6R) were constructed. Either the NH(2)-terminal (chimera RILLIFdeltaI) or the COOH-terminal LIFR CBM (chimera RILLIFdeltaII) were replaced by the structurally related CBM of the IL-6R which does not bind LIF. Chimera RILLIFdeltaI is functionally inactive, whereas RILLIFdeltaII binds LIF and mediates signalling as efficiently as the wild-type LIFR. Deletion mutants of the LIFR revealed that both the NH(2)-terminal CBM and the Ig-like domain of the LIFR are involved in LIF binding, presumably via the LIF site III epitope. The main function of the COOH-terminal CBM of the LIFR is to position the NH(2)-terminal CBM and the Ig-like domain, so that these can bind to LIF. In analogy to a recently published model of the IL-6R complex, a model of the active LIFR complex is suggested which positions the COOH-terminal CBM at LIF site I and the NH(2)-terminal CBM and the Ig-like domain at site III. An additional contact is postulated between the Ig-like domain of gp130 and the NH(2)-terminal CBM of the LIFR.
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PMID:The upper cytokine-binding module and the Ig-like domain of the leukaemia inhibitory factor (LIF) receptor are sufficient for a functional LIF receptor complex. 1181 36

Ciliary neurotrophic factor (CNTF) is a member of the gp130 family of cytokines. The functional receptor complex of CNTF is composed of the CNTF receptor alpha (CNTFR), gp130 and the leukemia inhibitory factor receptor (LIFR). Three regions on CNTF have been identified as binding sites for its receptors. The ligand-receptor interactions are mediated through the cytokine binding domains (CBDs) and/or the immunoglobulin-like domains of the receptors. However, in the case of CNTF, the precise nature of the protein-protein contacts in the signaling complex has not yet been resolved. In this study, we provide the first demonstration that the membrane distal CBD (CBD1) of LIFR associates in vitro with soluble CNTFR in the absence of CNTF. Moreover, purified CBD1 partially blocks CNTF signaling, but not that of interleukin-6 or LIF, in human embryonal carcinoma cell line Ntera/D1 cells. These data raise the possibility that LIFR has the capability to form a ligand-free complex with CNTFR.
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PMID:Membrane distal cytokine binding domain of LIFR interacts with soluble CNTFR in vitro. 1194 54

Human ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that exerts a neuroprotective effect in multiple sclerosis and amyotrophic lateral sclerosis. Clinical application of human CNTF, however, was prevented by high toxicity at higher dosages. Human CNTF elicits cellular responses by induction of a receptor complex consisting of the CNTF alpha-receptor (CNTFR), which is not involved in signal transduction, and the beta-receptors gp130 and leukemia inhibitory factor receptor (LIFR). Previous studies with rat CNTF demonstrated that rat CNTF is unable to interact with the human interleukin-6 alpha-receptor, whereas at high concentrations, it can directly induce a signaling heterodimer of human gp130 and human LIFR in the absence of the CNTF receptor. Here, we demonstrate that human CNTF cannot directly induce a heterodimer of human gp130 and LIFR. However, human CNTF can use both the membrane-bound and the soluble human IL-6R as a substitute for its cognate alpha-receptor and thus widen the target spectrum of human CNTF. Engineering a CNTFR-specific human CNTF variant may therefore be a prerequisite to improving the safety profile of CNTF.
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PMID:Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF. 1264 74

In contrast to other hematopoietic cytokine receptors, the leukemia inhibitory factor receptor (LIFR) possesses two cytokine binding modules (CBMs). Previous studies suggested that the NH(2)-terminal CBM and the Ig-like domain of the LIFR are most important for LIF binding and activity. Using the recently engineered designer cytokine IC7, which induces an active heterodimer of the LIFR and gp130 after binding to the IL-6R, and several receptor chimeras of the LIFR and the interleukin-6 receptor (IL-6R) carrying the CBM of the IL-6R in place of the COOH-terminal LIFR CBM, we could assign individual receptor subdomains to individual binding sites of the ligand. The NH(2)-terminal CBM and the Ig-like domain of the LIFR bind to ligand site III, whereas the COOH-terminal CBM contacts site I. Furthermore, we show that LIFR mutants carrying the IL-6R CBM instead of the COOH-terminal CBM can replace the IL-6R by acting as an alpha-receptor for IL-6. However, in situations where a signaling competent receptor is bound at IL-6 site I, ligand binding to site III is an absolute requirement for participation of the receptor in a signaling heterodimer with gp130; i.e., a functional receptor complex of IL-6 type cytokines cannot be assembled solely via site I and II as in the growth hormone receptor complex.
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PMID:Analysis of the leukemia inhibitory factor receptor functional domains by chimeric receptors and cytokines. 1273 65

Nerve growth factor (NGF) is required for the development of sympathetic neurons and subsets of sensory neurons. Our current knowledge on the molecular mechanisms underlying the biological functions of NGF is in part based on the studies with PC12 rat pheochromocytoma cells, which differentiate into sympathetic neuron-like cells upon NGF treatment. Here we report that the expression of leukemia inhibitory factor receptor (LIFR), one of the signaling molecules shared by several neuropoietic cytokines of the interleukin-6 family, is specifically up-regulated in PC12 cells following treatment with NGF. Attenuation of LIFR signaling through stable transfection of antisense- or dominant negative-LIFR constructs enhances NGF-induced neurite extension in PC12 cells. On the contrary, overexpression of LIFR retards the growth of neurites. More importantly, whereas NGF-induced Rac1 activity is enhanced in antisense-LIFR and dominant negative-LIFR expressing PC12 cells, it is reduced in LIFR expressing PC12 cells. Following combined treatment with NGF and ciliary neurotrophic factor, sympathetic neurons exhibit attenuated neurite growth and branching. On the other hand, in sympathetic neurons lacking LIFR, neurite growth and branching is enhanced when compared with wild type controls. Taken together, our findings demonstrate that LIFR expression can be specifically induced by NGF and, besides its known function in cell survival and phenotype development, activated LIFR signaling can exert negative regulatory effects on neurite extension and branching of sympathetic neurons.
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PMID:Leukemia inhibitory factor receptor signaling negatively modulates nerve growth factor-induced neurite outgrowth in PC12 cells and sympathetic neurons. 1287 77

There is a growing recognition of choroid plexus functioning as a source of neuropeptides, cytokines and growth factors in cerebrospinal fluid (CSF) with diffusional access into brain parenchyma. In this study, choroid plexus and other components of the CSF circulatory system were investigated by Western blotting, reverse transcriptase polymerase chain reaction and immunohistochemistry for production of interleukin-6-related cytokines characterized by neuroactivity [cardiotrophin-1 (CT-1), ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin M] and signaling through the gp130/leukemia inhibitory factor receptor-beta receptor heterodimer. Western blot analysis showed that CT-1 was the only cytokine family member detectable in adult rat choroid plexus, as in leptomeninges. The specificity of detection was verified with blots of the same tissues from CT-1-deficient mice. Levels of both CT-1 mRNA and protein were constitutively high in rat from birth through adulthood in choroid plexus, up-regulated postnatally in leptomeninges and undetectable in brain parenchyma. Using antigen retrieval, CT-1 immunolocalized to choroid epithelial cells in all choroid plexuses in addition to leptomeninges (arachnoid and pial-glial membranes). Ependymal cells lining the ventricular neuroaxis, unlike the central canal, were also CT-1-immunoreactive. Western blots indicated rat choroid epithelial cells express and release CT-1 immunoreactivity under defined culture conditions and also revealed the presence of a CT-1-like protein in human choroid plexus and CSF. Previously, CT-1 has been conceptualized to function as a target-derived factor for PNS neurons. Our study clearly demonstrates production of CT-1 in the postnatal and adult CNS, specifically by cell types comprising the blood-CSF barrier, and its accumulation in ventricular ependyma. This finding has broad implications for CT-1 functioning apart from other leukemia inhibitory factor receptor ligands as a CSF-borne signal of brain homeostasis, one possibly involving regulation of the barrier itself, the ependyma or target cells in the surrounding parenchyma, including the subventricular zone. A rationale for studies examining CT-1-deficient mice in these respects is provided by the data.
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PMID:Cardiotrophin-1 in choroid plexus and the cerebrospinal fluid circulatory system. 1521 67

The aim of this study was to determine the effects of mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) on development of porcine parthenotes and nuclear transferred embryos, and on their expression of implantation-related genes. In the presence of bovine serum albumin, mGM-CSF did not increase the percentage of oocytes that developed to the blastocyst stage and at day 7 did not increase cell numbers of embryos. Addition of 2 ng/ml GM-CSF to protein-free culture medium significantly increased the compaction and blastocoel formation of 1- to 2-cell parthenotes developing in vitro. However, total cell numbers were not increased when they were cultured in the presence of GM-CSF. Semi-quantitative reverse transcriptase polymerase chain reaction revealed that mGM-CSF enhances mRNA expression of the leukemia inhibitory factor receptor, but does not influence interleukin-6 or sodium/glucose co-transporter protein gene expression in blastocyst stage parthenotes. These results suggest that mGM-CSF may enhance viability of porcine embryos developing in vitro in a defined culture medium.
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PMID:Mouse granulocyte-macrophage colony-stimulating factor enhances viability of porcine embryos in defined culture conditions. 1530 96

The interleukin-6 cytokine oncostatin M (OSM) induces potent growth-inhibitory and morphogenic responses in several different tumor cell types, highlighting the importance of OSM signaling mechanisms as targets for therapeutic intervention. The specific molecular pathways involved are not well understood, as OSM can signal through two separate heterodimeric receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) alpha and gp130/OSM receptor beta (OSMRbeta). In this investigation, we used a LIFR antagonist to help resolve signaling responses and identify patterns of gene expression elicited by the different receptor complexes. OSM-induced biological effects on breast tumor-derived cell lines were specifically mediated through the gp130/OSMRbeta complex. Each cytokine tested exhibited differential signaling capability and manifested both shared and unique patterns of gene activation, emphasizing compositional differences in activator protein-1 transcription factor activity and expression. In particular, OSM strongly activated the c-Jun NH(2)-terminal kinase (JNK) serine/threonine kinase and downstream components, including activating transcription factor (ATF)/cyclic AMP-responsive element binding protein family member, ATF3. JNK/stress-activated protein kinase kinase inhibition abrogated cell morphogenesis induced by OSM, indicating an important role for this pathway in OSM specificity. These findings identify a core signaling/transcriptional mechanism specific to the OSMRbeta in breast tumor cells.
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PMID:Oncostatin M (OSM) cytostasis of breast tumor cells: characterization of an OSM receptor beta-specific kernel. 1710 26


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