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)

During inflammatory states, hepatocytes are induced to synthesize and secrete a group of proteins called acute-phase proteins. It has recently been shown that besides interleukin-6 (IL-6), related cytokines such as leukemia inhibitory factor, oncostation M and interleukin-11 are also mediators of the hepatic acute-phase response. All these mediators belong to the hematopoietic family of alpha-helical cytokines. Here we show that an additional member of this cytokine family, ciliary neurotrophic factor (CNTF), induces the hepatic acute-phase protein genes haptoglobin, alpha 1-antichymotrypsin, alpha 2-macroglobulin and beta-fibrinogen in human hepatoma cells (HepG2) and in primary rat hepatocytes with a time course and dose-response comparable with that of IL-6. Our next aim was to define the receptor components used by CNTF on hepatic cells. Using a cell-free binding assay we exclude that CNTF binds to the 80 kDa IL-6 receptor, a protein with significant homology to the CNTF receptor which has recently been cloned from neuroblastoma cells. In human hepatoma cells (Hep3B) which lack the leukemia inhibitory factor receptor, CNTF was not able to induce acute-phase protein synthesis, indicating that this receptor protein may be part of the functional CNTF receptor on hepatic cells.
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PMID:Ciliary neurotrophic factor induces acute-phase protein expression in hepatocytes. 128 89

Although neurotrophic factors were originally isolated on the basis of their ability to support the survival of neurons, these molecules are now thought to influence many aspects of the development and maintenance of the nervous system. Identifying the receptors for these neurotrophic factors should aid in identifying the cells on which these factors act and in understanding their precise mechanisms of action. A "tagged-ligand panning" procedure was used to clone a receptor for ciliary neurotrophic factor (CNTF). This receptor is expressed exclusively within the nervous system and skeletal muscle. The CNTF receptor has a structure unrelated to the receptors utilized by the nerve growth factor family of neurotrophic molecules, but instead is most homologous to the receptor for a cytokine, interleukin-6. This similarity suggestes that the CNTF receptor, like the interleukin-6 receptor, requires a second, signal-transducing component. In contrast to all known receptors, the CNTF receptor is anchored to cell membranes by a glycosyl-phosphatidylinositol linkage.
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PMID:The receptor for ciliary neurotrophic factor. 164 65

Ciliary neurotrophic factor (CNTF) is a cytokine sharing structural and functional similarities with interleukin-6 (IL-6) and other helical cytokines that utilize the common signalling chain gp130. While IL-6 induces gp130 dimerization, CNTF, after the initial interaction with the specific, non-signalling receptor subunit, CNTFR, induces the formation of gp130/LIF-receptor heterodimers. Through immunoprecipitation experiments with tagged soluble receptor molecules, we recently demonstrated that IL-6 drives the formation of a hexameric receptor complex with a defined topology and composed of two IL-6, two IL-6R alpha and two gp130 molecules. Here, we apply the same strategy to study the assembly in vitro of the CNTF receptor complex. We present evidence that both the cytokine and the specific binding chain undergo dimerization in the presence of gp130. Furthermore, although gp130 and LIFR are able to bind independently to the CNTF/CNTFR sub-complex, they never form homodimers but only heterodimers. We propose that CNTF assembles a hexameric receptor complex composed of two CNTF, two CNTFR, one gp130 and one LIFR molecule, and present a model of the reciprocal interaction of these molecules based on similarities with the IL-6 hexameric complex.
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PMID:In vitro binding of ciliary neurotrophic factor to its receptors: evidence for the formation of an IL-6-type hexameric complex. 750 Mar 50

By rational mutagenesis, receptor-specific functional analysis, and visualization of complex formation in solution, we identified individual amino acid side chains involved specifically in the interaction of ciliary neurotrophic factor (CNTF) with CNTFR alpha and not with the beta-components, gp130 and LIFR. In the crystal structure, the side chains of these residues, which are located in helix A, the AB loop, helix B, and helix D, are surface accessible and are clustered in space, thus constituting an epitope for CNTFR alpha. By the same analysis, a partial epitope for gp130 was also identified on the surface of helix A that faces away from the alpha-epitope. Superposition of the CNTF and growth hormone structures showed that the location of these epitopes on CNTF is analogous to the location of the first and second receptor epitopes on the surface of growth hormone. Further comparison with proposed binding sites for alpha- and beta-receptors on interleukin-6 and leukemia inhibitory factor indicated that this epitope topology is conserved among helical cytokines. In each case, epitope I is utilized by the specificity-conferring component, whereas epitopes II and III are used by accessory components. Thus, in addition to a common fold, helical cytokines share a conserved order of receptor epitopes that is function related.
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PMID:Localization of functional receptor epitopes on the structure of ciliary neurotrophic factor indicates a conserved, function-related epitope topography among helical cytokines. 753 96

Ciliary neurotrophic factor (CNTF), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and oncostatin M (OSM) share functional properties, a predicted common helical framework, and partially identical receptor components. CNTF is a survival promoting factor for various types of neurons in vitro and in vivo. In the present study, structural features essential for the biological function of human CNTF were investigated. Several recombinant CNTF variants were constructed by PCR and expressed in E. coli. Their survival promoting activities were determined using cultures of embryonic chick and newborn rat dorsal root ganglion cells. Deletion of 14 N-terminal and 18 C-terminal amino acids significantly increased bioactivity compared to wild-type (wt) CNTF. Further truncation of the CNTF molecule at the N- or C-terminus resulted in a significant reduction or complete loss of activity. Substitution of two amino acids (Lys154Glu and Trp157Pro) abolished the survival promoting effect. Recently described analogous substitutions in IL-6 had resulted in a partial IL-6 receptor antagonist. However, the double substitution variant had no significant inhibitory effect on wtCNTF activity in assays with both wt and mutant factor. The CNTF variants constructed had almost identical effects on both chick and rat neurons indicating a close similarity of the avian and the mammalian CNTF receptor complex. The present results also demonstrate that a core segment of the CNTF molecule is indispensable for biological function. Analogous segments important for activity have already been identified in the related molecules IL-6, LIF, and OSM. Thus, our data confirm the close structural relationship of CNTF to these "neuropoietic" cytokines. In addition, they demonstrate that site-directed mutagenesis of recombinant human CNTF can yield molecules which show increased survival promoting activity on mammalian neurons.
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PMID:Site-directed mutagenesis of human CNTF: functional analysis of recombinant variants. 762 95

Ciliary neurotrophic factor (CNTF) has recently been found to share receptor components with, and to be structurally related to, a family of broadly acting cytokines, including interleukin-6, leukemia inhibitory factor, and oncostatin M. However, the CNTF receptor complex also includes a CNTF-specific component known as CNTF receptor alpha (CNTFR alpha). Here we describe the molecular cloning of the human and mouse genes encoding CNTFR. We report that the human and mouse genes have an identical intron-exon structure that correlates well with the domain structure of CNTFR alpha. That is, the signal peptide and the immunoglobulin-like domain are each encoded by single exons, the cytokine receptor-like domain is distributed among 4 exons, and the C-terminal glycosyl phosphatidylinositol recognition domain is encoded by the final coding exon. The position of the introns within the cytokine receptor-like domain corresponds to those found in other members of the cytokine receptor superfamily. Confirming a recent study using radiation hybrids, we have also mapped the human CNTFR gene to chromosome band 9p13 and the mouse gene to a syntenic region of chromosome 4.
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PMID:Genomic organization and chromosomal localization of the human and mouse genes encoding the alpha receptor component for ciliary neurotrophic factor. 777 13

Ciliary neurotrophic factor (CNTF) is a 22-kDa protein predicted to share with leukemia inhibitory factor (LIF) and interleukin-6 a common amphipathic helical domain. Consistent with this prediction, the CNTF receptor complex is composed of the CNTF alpha receptor, the LIF beta receptor and gp130 a signalling molecule for LIF and interleukin-6. The major sources of synthesis of CNTF are Schwann cells and astrocytes, but it remains unclear how much CNTF is released from these glial cells and by what mechanism. In vitro, CNTF supports the survival of all classes of peripheral nervous system neurons plus many CNS neurons, induces neurite outgrowth, promotes a cholinergic phenotype in sympathetic neurons and arrests division of neuronal precursor cells. Several cell lines also respond to CNTF. In vivo, CNTF rescues several types of neurons from axotomy-induced death. The functions of CNTF in the development and maintenance of the nervous system remain enigmatic.
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PMID:Ciliary neurotrophic factor: a review. 780 79

Recent efforts to understand the mechanism of action of CNTF have led to the identification of a three-component receptor complex for CNTF. The distributions of these receptor components explain the known target cell specificity of CNTF, and have also helped identify new and unexpected targets of CNTF action. In addition to including a CNTF-specific component, known as CNTFR alpha, the CNTF receptor complex utilizes two receptor components, gp130 and LIFR beta, that are shared with members of a family of broadly acting cytokines, including leukemia inhibitory factor (LIF) and interleukin-6 (IL6). The finding that the CNTF receptor complex shares components with this family of cytokines has led to the realization that CNTF should also be considered a cytokine--but one that differs from its relatives in that its actions are largely limited to cells of the nervous system due to the restricted expression of one of its receptor components, CNTFR alpha. CNTFR alpha does not play a direct role in signaling, but instead forms a complex with CNTF that promotes its binding to the signal transducing "beta" receptor components, gp130 and LIFR beta. Thus CNTF utilizes identical signal transducing receptor components in neurons that its relatives use on nonneuronal cells to elicit strikingly dissimilar responses, indicating that different cells interpret the same cell surface signal in dramatically different ways. The three CNTF receptor components are initially unassociated on the cell surface, and are brought together in step-wise fashion upon CNTF binding. CNTF first binds to CNTFR alpha, then recruits gp130, and finally complexes with LIFR beta. It is this last step in complex formation, involving heterodimerization between "beta" components, that activates intracellular signaling. Signal initiation is due to activation of members of a family of cytoplasmic tyrosine kinase, known as the Jak/Tyk kinases, which are preassociated with the beta components in an inactive state and then become activated upon beta component dimerization; the Jak/Tyk kinases, in turn, activate a variety of intracellular signaling molecules, such as members of the STAT family of DNA binding transcriptional activators. A detailed understanding of the mechanism of activation of the CNTF receptor complex has led to the realization that all members of the CNTF family of cytokines activate signaling in much the same way, by inducing either homo- or heterodimerization of beta receptor components and thus activation of the preassociated Jak/Tyk kinases; this mode of receptor activation may prove to be more generally applicable to all cytokine receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The tripartite CNTF receptor complex: activation and signaling involves components shared with other cytokines. 785 97

Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are cytokines that give rise to an identical set of tyrosine-phosphorylated proteins upon addition to responsive cells. One of these proteins is the interleukin-6 signal-transducing molecule gp130, which is required for signal transduction by both CNTF and LIF. Here we identify another prominent tyrosine-phosphorylated protein as LIF receptor (LIFR) beta, which was originally cloned as a LIF-binding protein. Cross-linking experiments with iodinated factors were carried out on a cell line responsive to CNTF and LIF, as well as on COS cells that were cotransfected with various combinations of gp130, LIFR beta, and CNTF receptor (CNTFR) alpha, the previously cloned CNTF-binding protein. These experiments reveal that LIF cross-links to LIFR beta alone, as well as to gp130 when it is coexpressed with LIFR beta. However, cross-linking of CNTF to LIFR beta and gp130 is only observed in the presence of CNTFR alpha. These and other data show that the two known LIF receptor components are recruited by CNTF and CNTFR alpha to form a trimeric CNTF receptor complex.
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PMID:Cross-linking identifies leukemia inhibitory factor-binding protein as a ciliary neurotrophic factor receptor component. 838 13

The ciliary neurotrophic factor (CNTF) receptor complex is shown here to include the CNTF binding protein (CNTFR alpha) as well as the components of the leukemia inhibitory factor (LIF) receptor, LIFR beta (the LIF binding protein) and gp130 [the signal transducer of interleukin-6 (IL-6)]. Thus, the conversion of a bipartite LIF receptor into a tripartite CNTF receptor apparently occurs by the addition of the specificity-conferring element CNTFR alpha. Both CNTF and LIF trigger the association of initially separate receptor components, which in turn results in tyrosine phosphorylation of receptor subunits. Unlike the IL-6 receptor complex in which homodimerization of gp130 appears to be critical for signal initiation, signaling by the CNTF and LIF receptor complexes depends on the heterodimerization of gp130 with LIFR beta. Ligand-induced dimerization of signal-transducing receptor components, also seen with receptor tyrosine kinases, may provide a general mechanism for the transmission of a signal across the cell membrane.
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PMID:LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. 839 97


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