Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An adult mouse liver cDNA library was screened with oligonucleotides corresponding to the conserved WSXWS motif of the haemopoietin receptor family. Using this method, cDNA clones encoding a novel receptor were isolated. The new receptor, named NR1, was most similar in sequence and predicted structure to the alpha-chain of the IL-6 receptor and mRNA was expressed in the 3T3-L1 pre-adipocytic cell line and in a range of primary tissues. Expression of NR1 in the factor-dependent haemopoietic cell line Ba/F3 resulted in the generation of low affinity receptors for IL-11 (Kd approximately 10 nM). The capacity to bind IL-11 with high affinity (Kd = 300-800 pM) appeared to require coexpression of both NR1 and gp130, the common subunit of the IL-6, leukaemia inhibitory factor (LIF), oncostatin M (OSM) and ciliary neurotrophic factor (CNTF) receptors. The expression of both NR1 and gp130 was also necessary for Ba/F3 cells to proliferate and M1 cells to undergo macrophage differentiation in response to IL-11.
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PMID:Cloning of a murine IL-11 receptor alpha-chain; requirement for gp130 for high affinity binding and signal transduction. 795 45

In this report we document the derivation of pluripotential embryonic stem (ES) cells in the absence of a feeder layer by supplementation of culture media with either ciliary neurotrophic factor or oncostatin M, or with a combination of interleukin-6 (IL-6) plus soluble interleukin-6 receptor (sIL-6R). These factors all activate gp130-associated signaling processes, as does the previously characterized ES cell maintenance factor Differentiation Inhibiting Activity (Leukemia Inhibitory Factor). In particular, the IL-6/sIL-6R complex is thought to act exclusively through gp130. All ES cell lines derived using IL-6/sIL-6R contributed extensively to chimeras and were transmitted through the germline at high frequency. These findings point to a pivotal role for gp130 in ES cell propagation and may be relevant to attempts to derive ES cells from species other than mouse.
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PMID:Derivation of germline competent embryonic stem cells with a combination of interleukin-6 and soluble interleukin-6 receptor. 795 76

The aim of our study was to evaluate whether ciliary neurotrophic factor (CNTF) can substitute for leukaemia inhibitory factor (LIF) in maintaining pluripotential embryonic stem (ES) cells in culture. Two subclones of D3 ES cells were used to assess cell proliferation and differentiation in the presence of CNTF, LIF or Buffalo rat liver (BRL) cell-conditioned medium, or in the absence of exogenous differentiation inhibiting factors. ES cells maintained in medium supplemented with CNTF for up to four weeks were injected into blastocysts to investigate their in vivo pluripotency in terms of chimaera formation. CNTF inhibited ES cell differentiation in a dose-dependent manner. The most effective concentration was 10 ng CNTF per ml of medium. The effects of CNTF on ES cell differentiation and proliferation were comparable to those of LIF at the same concentration. BRL cell-conditioned medium was less effective at preventing ES cell differentiation but induced their proliferation very markedly. Both ES cell clones efficiently formed chimaeras after long-term culture with CNTF as the only differentiation inhibiting agent. The ability of these ES cells to colonize the germ-line is the ultimate proof that CNTF can preserve the pluripotency of ES cells.
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PMID:Efficient generation of chimaeric mice using embryonic stem cells after long-term culture in the presence of ciliary neurotrophic factor. 802 94

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates various aspects of the immune response, acute-phase reaction and haematopoiesis (for reviews see refs 1, 2). In vitro, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and interleukin-11 display overlapping activities with IL-6. This functional redundancy may be explained by the interactions of specific binding receptors with a common signal-transducing receptor (gp130) (for reviews see refs 3, 4). To elucidate the unique function of IL-6 in vivo, we have disrupted the IL-6 gene by homologous recombination. IL-6-deficient mice develop normally. They fail to control efficiently vaccinia virus and infection with Listeria monocytogenes, a facultative intracellular bacterium. The T-cell-dependent antibody response against vesicular stomatitis virus is impaired. Further, the inflammatory acute-phase response after tissue damage or infection is severely compromised, whereas it is only moderately affected after challenge with lipopolysaccharide. We conclude that IL-6 production induced by injury or infection is an important in vivo SOS signal which coordinates activities of liver cells, macrophages and lymphocytes.
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PMID:Impaired immune and acute-phase responses in interleukin-6-deficient mice. 812 68

The development of motoneurons in the spinal cord is strongly dependent on their interactions with their target tissue, skeletal muscle, and with other cells of the central nervous system. The molecular nature of these interactions has remained obscure for many years. However, over the last few years, known growth factors have been shown to have biological activity on the survival of motoneurons, at least in culture. The factors that have been studied are members of the FGF family (fibroblast growth factors), the TGF-beta family (transforming growth factor-beta), CNTF (ciliary neurotrophic factor) and CDF-LIF (cholinergic development factor-leukaemia inhibitory factor). There are also strong reasons to suppose that at least one member of the neurotrophin family (the family that contains Nerve Growth Factor) is involved in motoneuron development. A more detailed analysis of the biological role of each of these factors should not only enlighten us as to the importance of cell-cell interactions in development of the motoneuron, but also open the way to attempts to slow motoneuron death in pathological situations, either in animals or in man.
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PMID:[Growth and survival factors of spinal motoneurons]. 824 22

We have examined whether activation of MAP kinases [or extracellular signal-regulated kinases (ERKs)] is required for the survival of rat sympathetic neurons by comparing the actions of three survival factors whose survival-promoting actions can be blocked by neutralizing Fab fragments to p21 ras (Nobes and Tolkovsky, 1995, Eur. J. Neurosci., 7, 344-350), nerve growth factor (NGF), the cytokines ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF), and the cyclic AMP analogue 4-(8-chlorophenylthio)cAMP (CPTcAMP). NGF-induced survival was accompanied by an intense (15- to 30-fold) and steady (> 24 h) activation of p44 and p42 ERKs which waned rapidly (t1/2 approximately 30 min) upon NGF withdrawal. However, concentrations of NGF that induced a weak (4- to 5-fold) stimulation of the ERKs were not sufficient to maintain long-term survival. Moreover, prolonged and intense stimulation of the ERKs by NGF for up to 15.5 h was unable to confer long-term survival, since withdrawal of NGF after this time resulted in neuronal death that was kinetically indistinguishable from the death of neurons that had not been exposed to NGF. By contrast, CNTF and LIF continued to support survival for up to 3 days after eliciting only transient (< 30 min and 1 h respectively) activation of p44 and p42 ERKs, while CPTcAMP induced survival for several days without any measurable activation of the ERKs. Taken together, these data suggest that ERK activation per se is neither necessary nor sufficient for survival and that alternative pathways exist for effecting long-term survival of rat sympathetic neurons.
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PMID:Activation of p44 and p42 MAP kinases is not essential for the survival of rat sympathetic neurons. 854 72

The cytokines interleukin (IL)-6, IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitor factor (LIF), oncostatin M (OSM) and probably the recently cloned cytokine cardiotrophin-1, signal, in combination with their specific receptors, through the common signal transducer gp130. Here, we report that the signaling activities of IL-6, IL-11, CNTF and OSM/LIF can be specifically blocked by different anti-gp130 monoclonal antibodies (mAb). Furthermore, we found two mAb, B-P8 and B-S12, which directly activate gp130 independently of the presence of cytokines or their receptors. This agonistic activity includes induction of cytokine-dependent cell proliferation and stimulation of acute-phase protein synthesis in liver cells. Compared to B-P8 mAb, the B-S12 mAb exhibited the strongest agonistic activity, while both mAb are synergistic in their action. This activity could not be blocked by inhibiting mAb against IL-6 and the IL-6 receptor. In contrast to F(ab')2 of B-S12 which still could activate gp130, Fab fragments completely lost their agonistic activity. Activation by tyrosine phosphorylation of the transcription factors Stat1 and APRF/Stat3 was also induced by B-S12 and B-P8, suggesting that both mAb induce homodimerization of gp130. Since hematopoietic stem cells express gp130 on their plasma membrane, it was anticipated that the agonistic anti-gp130 mAb could stimulate the proliferation of these stem cells. Indeed, B-S12 and B-P8 were able to stimulate CD34+ cells. In summary, our data show for the first time that mAb against gp130 can specifically block the action of distinct IL-6-type cytokines that signal through gp130. Such mAb might be of great value for therapeutic applications in diseases where a single cytokine action needs to be inhibited. In addition, the agonistic gp130 mAb may be used as growth factors for maintenance and expansion of stem cells prior to grafting.
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PMID:Interleukin-6 signal transducer gp130 has specific binding sites for different cytokines as determined by antagonistic and agonistic anti-gp130 monoclonal antibodies. 856 40

Oncostatin M (OSM) is structurally and functionally similar to leukaemia inhibitory factor (LIF), interleukin 6 (IL-6), interleukin 11 (IL-11) and ciliary neurotrophic factor (CNTF). We have previously shown that LIF stimulates proteoglycan release and suppresses proteoglycan synthesis in pig and goat cartilage explants. The aim of this study was to determine whether OSM and related cytokines influence proteoglycan metabolism in pig cartilage explants. Slices of pig articular cartilage were incubated for 6 days in serum free DMEM with or without cytokines. The total proteoglycan content in papain digested cartilage explants and medium was determined by the 1,9 dimethylmethylene blue method. Cytokine activity was assessed by determining the percentage release of total proteoglycan. To evaluate proteoglycan synthesis, cartilage was cultured for 48 h under the same conditions and in the final 6 h the tissue was cultured in sulphate free DMEM containing 35SO4. The radioactivity in the medium and tissue was determined in cetylpyridinium chloride precipitates. Biosynthetic activity was expressed as DPM per mg wet weight of cartilage. Dose dependent stimulation of proteoglycan release and suppression of proteoglycan synthesis were observed with rhOSM. IL-6, IL-11 and CNTF also inhibited proteoglycan synthesis in a dose dependent manner but the degree of inhibition was less than that for OSM and these cytokines had no significant effect on proteoglycan release. New biological effects have been identified for OSM and the related cytokines CNTF and IL-11. All three of these cytokines, like LIF and IL-6, suppress proteoglycan synthesis in pig cartilage explants. This common effect suggests that the gp130 subunit of the receptors for these cytokines may represent a common signalling pathway whereby proteoglycan synthesis is regulated. Whilst OSM and LIF stimulate proteoglycan catabolism; IL-6 IL-11 and OSM do not. Thus these effects are not always coupled and activation of gp130 alone may not be a sufficient signal for proteoglycan catabolism.
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PMID:Oncostatin M (OSM) stimulates resorption and inhibits synthesis of proteoglycan in porcine articular cartilage explants. 881 47

Immature cerebellar granule neurons die by apoptosis within 1 week in vitro unless maintained in depolarizing (high) concentrations of potassium (25 mM K+). Neurons allowed to survive and differentiate in high K+ medium for several days in vitro are still induced to undergo apoptosis when switched back to physiological (low) concentrations of K+ (5 mM). Here we have investigated the effects of various cytokines and growth factors in these two well-defined paradigms of neuronal apoptosis. Tumour necrosis factor-alpha, leukaemia inhibitory factor, ciliary neurotrophic factor, interleukin-10 and interleukin-13 delayed apoptosis and prolonged survival of cerebellar granule neurons maintained in low K+ medium. The effect observed required continuous exposure of the cultures to the cytokines and appeared not to involve modulation of Bcl-2 protein expression. Brain-derived neurotrophic factor accelerated neuronal death in low K+ medium. In contrast, when apoptosis of the neurons was precipitated by switching mature high K+ neurons to low K+ medium, neither tumour necrosis factor-alpha, leukaemia inhibitory factor, ciliary neurotrophic factor, interleukin-10 nor interleukin-13 prevented apoptosis. When testing the cytokines and growth factors for their capacity to alter N-methyl-D-aspartate receptor-mediated excitotoxicity of differentiated cerebellar granule neurons, no significant effect was observed. These data appear to define a maturation-dependent modulation of cerebellar granule cell survival by cytokines and neurotrophic factors that are expressed in a developmental pattern in the mammalian brain.
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PMID:Maturation-dependent modulation of apoptosis in cultured cerebellar granule neurons by cytokines and neurotrophins. 892 Dec 90

Receptors for many of the cytokines functioning in the haematopoietic system belong to the class I cytokine receptor family. In most cases these receptors share common signal transducing receptor components in the same family, which explains the functional redundancy of haematopoietic cytokines. Interleukin-6 and related cytokines, interleukin-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1, are all pleiotrophic, from the haematopoietic to the nervous system, and exhibit overlapping biological activities. Receptors for these cytokines fall into the class I cytokine receptor family. Functional receptor complexes for the interleukin-6 family of cytokines share a membrane glycoprotein 130 (gp130) as a critical component for signal transduction. In these receptor complexes, gp130 and ligand-specific chains possess no intrinsic tyrosine kinase domain but are associated with cytoplasmic tyrosine kinases. Ligand stimulation triggers homo- or heterodimerization of gp130, leading to activation of the associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. This paper reviews the recent progress in the study of gp130 and the background information from biomedical and biochemical viewpoints.
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PMID:The signal transducer gp130 is shared by interleukin-6 family of haematopoietic and neurotrophic cytokines. 907 25


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