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)

Gp130 is the signal transducing subunit of the interleukin-6 receptor. Signaling is initiated by the complex formation of gp130 with IL-6 bound to the IL-6 receptor (IL-6R). We have subdivided the extracellular domain of gp130 in two parts and expressed the mutant proteins as soluble IgG fusion proteins in COS-7 cells. By studying the formation of the ternary complex we show that the membrane distal half of gp130 which contains a cytokine receptor domain is responsible for the interaction with the IL-6/IL-6R complex. Interestingly this is the same region which is believed to be involved in specific recognition of the related cytokines LIF, OM, and probably also of CNTF and IL-11.
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PMID:The membrane distal half of gp130 is responsible for the formation of a ternary complex with IL-6 and the IL-6 receptor. 787 98

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

Ciliary neurotrophic factor (CNTF) is a trophic protein that promotes survival and/or differentiation of a variety of neuronal cell types including sensory, sympathetic, and motor neurons. CNTF, leukemia inhibitory factor (LIF), interleukin-6 (IL-6) and oncostatin M (OSM) share a predicted common helical framework and partially identical receptor components. In this study, we present the preparation and structure--functional analysis of recombinant human CNTF. The human CNTF gene was expressed under the control of the PL promoter in Escherichia coli, and the mutants were constructed by insertion, deletion and site-directed mutagenesis. The recombinant proteins were purified from bacteria via DEAE A-50 and Sephacryl S-200 chromatography, and their survival promoting activities were determined using cultures of embryonic chick dorsal root ganglion (DRG) neurons. Insertion at position 23 with APGL, or at position 79 with PRGA, or substitution of 162L163Q for PIDG resulted in proteins with no neurotrophic activity. However, insertion at position 186 with PRGI did not alter human CNTF activity. Deletion of the carboxy-terminal amino acid 186-200 did not reduce the biological activity, but elimination of the amino acid 162-186 abolished the activity. The mutant substituting of 17 Cys for Ser was found to display a biological activity equivalent to that of the wild type. Our data provided experimental confirmation for the structural prediction of CNTF.
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PMID:Preparation and a structure-function analysis of human ciliary neurotrophic factor. 860 71

Ciliary neurotrophic factor (CNTF) and interleukin-6 (IL-6) potentiate the elevation of serum corticosterone induced by suboptimal doses of interleukin-1 (IL-1). CNTF also potentiates IL-1-induced serum IL-6. Here, we report that four other cytokines (leukemia inhibitory factor [LIF], oncostatin M [OSM], interleukin-11 and cardiotrophin-1) also potentiated the elevation of serum corticosterone and IL-6 levels induced by IL-1. Furthermore, all the six cytokines studied induced the acute-phase protein serum amyloid A when administered alone. Because these cytokines differ both in structure and in function, but share gp130 as a subunit of their receptors, these results indicate that signaling through gp130 mediates potentiation of IL-1 activities. The potentiation of IL-1-induced serum corticosterone levels is not a consequence of the increased serum IL-6 observed after IL-1 administration. In fact, in IL-6 deficient mice, IL-1 increased serum corticosterone to a level comparable to that observed in wild-type mice. Thus, either endogenous IL-6 does not mediate IL-1-induced corticosterone increase, or its role may be fulfilled by other cytokines. To the extent that gp130-dependent cytokines may serve this role, they may be important feedback regulators of inflammation through the activation of the hypothalamus-pituitary-adrenal axis and the potentiation of acute-phase protein synthesis.
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PMID:Six different cytokines that share GP130 as a receptor subunit, induce serum amyloid A and potentiate the induction of interleukin-6 and the activation of the hypothalamus-pituitary-adrenal axis by interleukin-1. 863 32

We examined the massive early cell death that occurs in the ventral horn of the cervical spinal cord of the chick embryo between embryonic days 4 and 5 (E4 and E5). Studies with immunohistochemical, in situ hybridization, and retrograde-tracing methods revealed that many dying cells express Islet proteins and Lim-3 mRNA (motoneuron markers) and send their axons to the somatic region of the embryo before cell death. Together, these data strongly suggest that the dying cells are somatic motoneurons. Cervical motoneurons die by apoptosis and can be rescued by treatment with cycloheximide and actinomycin D. Counts by motoneuron numbers between E3.5 and E10 revealed that, in addition to cell death between E4 and E5, motoneuron death also occur between E6 and E10 in the cervical cord. Studies with [3H]thymidine autoradiography and morphological techniques revealed that in the early cell-death phase (E4-E5), genesis of motoneurons, axonal elongation, and innervation of muscles is still ongoing. However, studies with [3H]thymidine autoradiography also revealed that the cells dying between E4 and E5 become postmitotic before E3.5. Increased size of peripheral targets, treatment with neuromuscular blockade, and treatment with partially purified muscle or brain extracts and defined neurotropic agents, such as NGF, BDNF, neurotrophin-3, CNTF, bFGF, PDGF, S100-beta, activin, cholinergic differentiation factor/leukemia inhibitory factor, bone morphogenetic protein-2, IGF-I, interleukin-6, and TGF-beta 1, were all ineffective in rescuing motoneurons dying between E4 and E5. By contrast, motoneurons that undergo programmed cell death at later stages (E6-E10) in the cervical cord are target-dependent and respond to activity blockade and trophic factors. Experimental approaches revealed that early cell death also occurs in a notochord-induced ectopic supernumerary motoneuron column in the cervical cord. Transplantation of the cervical neural tube to other segmental regions failed to alter the early death of motoneurons, whereas transplantation of other segments to the cervical region failed to induce early motoneuron death. These results suggest that the mechanisms that regulate motoneuron death in the cervical spinal cord between E4 and E5 are independent of interactions with targets. Rather, this novel type of cell death seems to be determined by signals that either are cell-autonomous or are derived from other cells within the cervical neural tube.
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PMID:A novel type of programmed neuronal death in the cervical spinal cord of the chick embryo. 864 12

Fifty-seven patients with amyotrophic lateral sclerosis (ALS) were randomly assigned to receive 0.5, 1, 3, 7, 10, or 30 micrograms/kg recombinant human ciliary neurotrophic factor (rHCNTF) or placebo subcutaneously 3 times a week for 2 weeks. Dose-limiting toxicity, consisting of febrile reactions in some patients, fatigue, and nonproductive cough, was observed at a dose level of 30 micrograms/kg. Dose-related changes in parameters of the acute-phase response were noted, consistent with the relationship of CNTF and its receptor system to the cytokine interleukin-6 (IL-6) and its receptor. No adverse neurologic consequences of rHCNTF administration were observed. Antibodies to rHCNTF were observed in sera of most patients tested after 2 weeks of continuous treatment and 4 weeks' withdrawal period. rHCNTF was safe and tolerated within acceptable limits when administered to patients with ALS in this study at doses of up to 30 micrograms/kg 3 times a week for 2 weeks. Further studies to explore the efficacy of rHCNTF in the treatment of human motor neuron diseases are justified.
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PMID:A phase I study of recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis. The ALS CNTF Treatment Study (ACTS) Phase I-II Study Group. 868 12

Ciliary neurotrophic factor (CNTF), leukaemia inhibitory factor (LIF), oncostatin M (OSM), interleukin-6 (IL-6), and interleukin-11 (IL-11) are structurally and functionally related cytokines. We compared their survival-promoting activities on embryonic chick and newborn rat dorsal root ganglion (DRG) neurones. Human CNTF showed the well known trophic effect on both chick and rat DRG neurones. Human and murine LIF and, at unphysiologically high doses, human OSM were trophic for rat neurones, but failed to promote chick DRG cell survival. Human IL-11, murine IL-6 and human IL-6 did not improve chick or rat DRG neurone survival; soluble human IL-6 receptor alpha did not increase sensitivity to human IL-6. Thus, human CNTF as well as murine and human LIF had special neurotrophic properties compared with other related cytokines.
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PMID:Human CNTF and related cytokines: effects on DRG neurone survival. 874 40

Ciliary neurotrophic factor (CNTF), a member of the interleukin-6 (IL-6) superfamily, has recently been shown to induce several inflammatory responses when administered to healthy animals, including induction of fever and a hepatic acute phase protein response. In the present report, 250 micrograms.kg body wt-1.day-1 of recombinant rat CNTF or murine IL-6 were repeatedly administered to healthy mice over a 7-day period in an effort to compare biological responses. In addition to its in vivo capacity to elicit a hepatic acute phase response, administration of CNTF, but not IL-6, produced profound anorexia and lean tissue wasting in mice. In C57B1/6 mice, 7 days of CNTF administration led to a 21% loss in carcass protein content, resulting from carcass protein breakdown rates being increased 218% over freely fed controls (both P < 0.01). Protein synthesis rates in carcass protein were also increased in CNTF-treated mice compared with both freely fed animals and mice pair-fed equivalent quantities of food. In contrast, administration of equivalent quantities of murine IL-6 had no effect on food intake or body weight in mice, although IL-6 produced a similar hepatic acute phase response, as determined by increases in serum amyloid P and seromucoid fraction and increases in total hepatic protein synthesis. However, when CNTF was coincubated with extensor digitorum longus muscles from juvenile rats in vitro, rates of total muscle and myofibrillar protein degradation and muscle protein synthesis were unchanged. We conclude that CNTF can regulate in vivo both skeletal muscle remodeling as well as the distant anorexia and hepatic acute phase protein responses. In the case of skeletal muscle, these actions are both indirect and independent of the associated anorexia. These properties of CNTF are distinct from IL-6, which when administered to the mouse at these doses is neither anorexigenic nor cachexia producing.
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PMID:Ciliary neurotrophic factor is catabolic and shares with IL-6 the capacity to induce an acute phase response. 876 Feb 19

Interleukin-6 (IL-6) plays a central role in the pathogenesis of multiple myeloma, acting as both a growth and a survival factor for myeloma cells. A series of IL-6 receptor antagonists that are IL-6 variants has been recently obtained, the affinity of which for the ligand-specific receptor chain IL-6R alpha has been maintained or even increased, but the signaling of which is impaired by not being able to bind and/or dimerize the signaling chain gp130. Although IL-6 antagonists have been shown to inhibit the growth of IL-6-dependent myeloma, no information has been gathered on their ability to induce myeloma cell death. We show here that IL-6 receptor antagonists are pro-apoptotic factors for the IL-6-dependent human myeloma cell line XG-1. Their capacity to induce cell death is in direct relation to their affinity for IL-6R alpha, degree of gp130 binding impairment, and efficiency to inhibit intracellular signaling events. Interestingly, the most potent pro-apoptotic molecule, Sant7, counteracts the protective autocrine effect exercised by the limited amounts of IL-6 produced by XG-1 cells and is thus able to induce cell death at higher rate than just IL-6 deprivation. These findings are particularly relevant for the therapy of multiple myeloma.
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PMID:Interleukin 6 receptor superantagonists are potent inducers of human multiple myeloma cell death. 879 94

Ciliary neurotrophic factor (CNTF), a multipoietic factor, on a variety of neurons, prevents axotomy-induced motoneuron loss and can improve the outcome of murine motor neuron disease (MND). We carried out a study to determine whether other cytokines rescue spinal motoneurons from axotomy-induced cell death. Unilateral sciatic nerve was transected in neonatal rats. Two doses of recombinant murine cholinergic differentiation factor/leukemia inhibitory factor (CDF/LIF), recombinant rat CNTF, recombinant human granulocyte-colony stimulating factor (G-CSF), recombinant human interleukin-6 (IL-6), recombinant human tumor necrosis factor beta (TNF beta), or vehicle were administered daily for 2 weeks by intraperitoneal injection. After treatment, the number of spinal motoneurons was determined at the level of L4-5 segments. In comparison with vehicle, the higher doses of CDF/LIF, CNTF, and IL-6, and the lower doses of CDF/LIF and IL-6 significantly retarded the loss of motoneurons. G-CSF and TNF beta failed to inhibit motoneuron death. CDF/LIF and IL-6 rescued motoneurons from the retrograde death following axotomy, in a similar manner to CNTF. These results provide evidence that several cytokines may have therapeutic potential in human axonopathy or MND.
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PMID:Neuroprotective effect of various cytokines on developing spinal motoneurons following axotomy. 886 65


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