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)

A family of cytokines [IL-6, IL-11, oncostatin M (OM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotrophin-1] involved in various inflammatory or tumoral diseases share the same gp130 signal transducer chain. The complex formed with their specific receptors associates with a common transducing gp130 membrane protein (gp130) resulting in the formation of high avidity receptor and activation of tyrosine kinases. With the view of identifying gp130 domains specifically involved in IL-6 signalling, the authors prepared 37 new anti-gp130 mAb and analysed the structure-function relationship of the molecule. By cross-competition ELISA, the mAb were classified in 10 subgroups called A to J. By ELISA and BIAcore analysis, the mAb were found to recognize at least 18 antigenic specificities of the gp130 chain. The mAb reacted against the soluble and the membrane forms of gp130 as well. Their ability to inhibit the proliferation of the human myeloma cell line XG-4 of which the growth is strictly dependent on the presence of either exogenous IL-6, or LIF, or OM, or CNTF was studied. Besides mAb with no evident neutralizing effect (G and H) and mAb which neutralized equally well the activity of all tested cytokines (all mAb of groups A, I and J), some showed a selective effect. Those of group F inhibited also the proliferation induced by the 4 cytokines, but more specifically that dependent on the CNTF. mAb of groups B and E specifically inhibited the growth induced by IL-6, whereas those of group C inhibited that induced by LIF and OM. These results show the presence of different gp130 epitopes specifically involved in the signaling induced by the cytokines of the gp130 family. In ELISA, only mAb of group B and E were found to inhibit the binding of the IL-6-IL-6R complex to gp130, showing that they identified one or two domains of gp130 involved in its interaction with the IL-6-IL-6R complex. Precise identification of this(ese) epitope(s) would be useful to better understand the mechanisms of the IL-6 signalling.
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PMID:Specific inhibition of IL-6 signalling with monoclonal antibodies against the gp130 receptor. 911 31

The low-affinity leukaemia inhibitory factor receptor (LIF-R) is a component of cell-surface receptor complexes for the multifunctional cytokines leukaemia inhibitory factor, ciliary neurotrophic factor, oncostatin M and cardiotrophin-1. Both soluble and transmembrane forms of the protein have been described and several LIF-R mRNAs have been reported previously. In order to determine the coding potential of LIF-R mRNAs we have isolated and characterized the mouse LIF-R gene. mRNA encoding soluble LIF-R (sLIF-R) is formed by inclusion of an exon in which polyadenylation signals are provided by a B2 repeat. This exon is located centrally within the LIF-R gene but is excluded from the transmembrane LIF-R mRNA by alternative splicing. The transmembrane receptor is encoded by 19 exons distributed over 38 kb. Two distinct 5' non-coding exons have been identified, indicating the existence of alternative promoters. One of these is G/C rich and possesses a consensus initiator sequence as well as potential Sp1 binding sites. Expression of exon 1 from this promoter occurs in a wide variety of tissues, whereas expression of the alternative 5' untranslated region (exon 1a) is normally restricted to liver, the principal source of sLIF-R. During pregnancy expression of exon 1a becomes detectable also in the uterus. Expression of exon 1a increases dramatically during gestation and is accompanied by a similar quantitative rise in expression of sLIF-R mRNA. These findings establish that expression of LIF-R is under complex transcriptional control and indicate that regulated expression of the soluble cytokine receptor isoform may be due principally to an increase in the activity of a dedicated promoter.
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PMID:Structure of the mouse leukaemia inhibitory factor receptor gene: regulated expression of mRNA encoding a soluble receptor isoform from an alternative 5' untranslated region. 939 34

Leukemia Inhibitory Factor (LIF) has a wide variety of biological activities. It regulates the differentiation of embryonic stem cells, neural cells, osteoblasts, adipocytes, hepatocytes and kidney epithelial cells. It also triggers the proliferation of myoblasts, primordial germ cells and some endothelial cells. Many of these biological functions parallel those of interleukin-6, Oncostatin M, ciliary neurotrophic factor, interleukin-11 and cardiotrophin-1. These structurally related cytokines also share subunits of their receptors which could partially explain the redundancy in this system of soluble mediators. In vivo LIF proves important in regulating the inflammatory response by fine tuning of the delicate balance of at least four systems in the body, namely the immune, the hematopoietic, the nervous and the endocrine systems. Although we are far from its therapeutic applications, the fast increasing knowledge in this field may bring new insights for the understanding of the cytokine biology in general.
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PMID:Leukemia inhibitory factor: part of a large ingathering family. 950 97

Recent progress has revealed similarities between the receptors and signaling systems used by neurotrophic factors as compared to other growth factors and cytokines. The neurotrophins use a family of receptor tyrosine kinases known as the Trk receptors, whereas ciliary neurotrophic factor (CNTF) uses a "cytokine receptor" system that shares receptor components with a number of distantly related cytokines. We have used a human embryonal carcinoma cell line and human leukemia cell lines to examine the actions of the neurotrophins and CNTF on cellular differentiation. Our findings demonstrate that specific combinations of neurotrophic factors are required to influence the neuronal progenitor cells to become postmitotic mature CNS neurons. Such synergistic interactions may play an important role in modulating the differentiation of a wide assortment of neuronal precursors in the developing nervous system. Furthermore, our studies with leukemia cells suggest that neurotrophic factors may play a similar role in hematopoietic differentiation and that these factors may have therapeutic application in leukemia differentiation.
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PMID:The neurotrophins and neuropoietic cytokines: two families of growth factors acting on neural and hematopoietic cells. 962 41

The acute phase response to inflammation is mediated in part by the endogenous production of pro-inflammatory cytokines. Interleukin 6 (IL-6) and members of its superfamily, including ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF) have been implicated as primary mediators of the hepatic acute phase response. In the present report, mice suffering a turpentine-induced myositis were passively immunized with antibodies against either IL-6, CNTF or LIF. Passive immunization against IL-6 attenuated the anorexia and completely prevented the hypoalbuminaemia, and increases in the serum concentration of the acute phase reactants, amyloid P, amyloid A and seromucoid. In contrast, passive immunization against either CNTF or LIF failed to modulate the anorexia, weight loss or hepatic acute phase protein responses. The findings suggest that IL-6, but not other members of its superfamily, is primarily responsible for the hepatic acute phase response, and contributes to the anorexia, associated with turpentine-induced myositis.
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PMID:Interleukin 6, but not ciliary neurotrophic factor or leukaemia inhibitory factor, is responsible for the acute phase response to turpentine-induced myositis. 963 32

A model of spinal trauma was developed where spinal neurones of adult mice were exposed to the excitotoxic glutamate analogue beta-N-oxylamino-L-alanine (L-BOAA). After 24 h, the injured neurones received a single dose of [125I]-LIF at the same site of the spinal cord, and 2 h later, tissues were removed to assess the distribution of leukaemia inhibitory factor (LIF). There was a significant increase in LIF binding to the injured region of the spinal cord over saline controls, and this corresponded with a significant increase in LIF mRNA expression in the same region of the cord. There was a change in the expression of ciliary neurotrophic factor, but the expression of cardiotrophin-1 (CT-1) and the common receptor subunit LIF receptor beta (LIFRbeta) did not change after neurotoxin treatment. The results add to the evidence that LIF plays a significant role in the response of adult neuronal tissue to injury.
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PMID:Leukaemia inhibitory factor (LIF) production in a mouse model of spinal trauma. 967 74

Sensory neurons isolated from dorsal root ganglia of postnatal mice were analysed for cell surface p75, using fluorescent antibody staining with flow cytometry. They were found to follow a single bell-shaped distribution of p75 level, with no discrete group of p75-negative neurons. Sensory neurons were then separated by fluorescence-activated cell sorting into high- and low-p75 populations, consisting of cells within the highest and lowest 15th percentiles, respectively, of p75 expression levels. The sorted neurons were tested for trkA staining. All high-p75 neurons were positive for trkA, while many low-p75 cells were negative for trkA. The sorted neurons were placed in culture, and their survival in the absence and presence of various neurotrophins was measured. Low-p75 cells were found to have enhanced survival in the absence of neurotrophins, while cells with high p75 levels had reduced survival, compared to the overall population. Almost all high-p75 neurons were rescued with nerve growth factor, whereas less than half of the low-p75 cells were rescued. The slope of the dose response to nerve growth factor did not differ markedly between high- and low-p75 cells. High-p75, but not low-p75, neurons were responsive to neurotrophin-3. There was only a small response to either brain-derived neurotrophic factor or neurotrophin-4 in both high- and low-p75 neurons. All low-p75 neurons, and 68% of high-p75 neurons, survived in the presence of ciliary neurotrophic factor. These results, while consistent with our hypothesis that p75 may act as a death factor in postnatal sensory neurons, also imply a role for p75 in the modulation of trk responsiveness to neurotrophins. They also indicate overlapping neurotrophin responses in sensory neurons, especially in those with high p75 levels. A large proportion of low-p75 cells were not responsive to any of the nerve growth factor-related neurotrophins, suggesting an important role for cytokines such as ciliary neurotrophic factor and leukaemia inhibitor factor in the survival of sensory neurons.
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PMID:Rescue of dorsal root sensory neurons by nerve growth factor and neurotrophin-3, but not brain-derived neurotrophic factor or neurotrophin-4, is dependent on the level of the p75 neurotrophin receptor. 968 65

The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1. These so-called IL-6-type cytokines play an important role in the regulation of complex cellular processes such as gene activation, proliferation and differentiation. The current knowledge on the signal-transduction mechanisms of these cytokines from the plasma membrane to the nucleus is reviewed. In particular, we focus on the assembly of receptor complexes after ligand binding, the activation of receptor-associated kinases of the Janus family, and the recruitment and phosphorylation of transcription factors of the STAT family, which dimerize, translocate to the nucleus, and bind to enhancer elements of respective target genes leading to transcriptional activation. The important players in the signalling pathway, namely the cytokines and the receptor components, the Janus kinases Jak1, Jak2 and Tyk2, the signal transducers and activators of transcription STAT1 and STAT3 and the tyrosine phosphatase SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase] are introduced and their structural/functional properties are discussed. Furthermore, we review various mechanisms involved in the termination of the IL-6-type cytokine signalling, namely the action of tyrosine phosphatases, proteasome, Jak kinase inhibitors SOCS (suppressor of cytokine signalling), protein inhibitors of activated STATs (PIAS), and internalization of the cytokine receptors via gp130. Although all IL-6-type cytokines signal through the gp130/Jak/STAT pathway, the comparison of their physiological properties shows that they elicit not only similar, but also distinct, biological responses. This is reflected in the different phenotypes of IL-6-type-cytokine knock-out animals.
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PMID:Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. 971 87

To investigate when the neurotrophic cytokines ciliary neurotrophic factor (CNTF), leukaemia inhibitory factor (LIF), oncostatin-M (OSM), interleukin-6 (IL-6) and cardiotrophin-1 (CT-1) act on developing sensory neurones and whether they co-operate with neurotrophins in regulating neuronal survival, we studied the in vitro trophic effects of these factors on two well-characterized populations of cranial sensory neurones at closely staged intervals throughout embryonic development. The cutaneous sensory neurones of the trigeminal ganglion, which show an early, transient survival response to BDNF and NT3 before becoming NGF-dependent, were supported by CNTF, LIF, OSM and CT-1 during the late fetal period, several days after the neurones become NGF-dependent. At this stage of development, these cytokines promoted the survival of a subset of NGF-responsive neurones. The enteroceptive neurones of the nodose ganglion, which retain dependence on BDNF throughout fetal development, were supported throughout their development by CNTF, LIF, OSM and CT-1, and displayed an additional survival response to IL-6 in the late fetal period. These findings indicate that populations of sensory neurones display different developmental patterns of cytokine responsiveness and show that embryonic trigeminal neurones pass through several phases of differing neurotrophic factor survival requirements.
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PMID:Cytokines promote the survival of mouse cranial sensory neurones at different developmental stages. 974 28

Selective death of magnocellular vasopressinergic neurons in the hypothalamus has been reported in cases of hereditary and idiopathic diabetes insipidus and after experimental lesions of the hypothalamo-neurohypophyseal pathway. To identify trophic factors that promote survival of these neurons, an in vitro model system was established in which organotypic cultures of the rat hypothalamic paraventricular nucleus were maintained in chemically-defined medium. We observe that the majority of magnocellular vasopressinergic neurons die in these cultures, while other cell populations such as corticotrophin-releasing factor producing parvicellular and oxytocin producing magnocellular cells retain a well preserved cytoarchitectonic organization. Degenerating vasopressinergic cells exhibit morphological signs of apoptosis and stained positively when analysed by the terminal deoxynucleotidyl transferase biotinylated dUTP nick end-labelling assay. Partial survival of vasopressinergic neurons occurred after co-culturing the paraventricular nucleus with neurohypophyseal explants, indicating that target-derived factors may be required for the survival of these neurons. Cell survival is dramatically increased by the administration of ciliary neurotrophic factor and leukemia inhibiting factor, but not by interleukin 6 or the members of the neurotrophin family. Reverse transcription-polymerase chain reaction followed by Southern analysis shows the presence of ciliary neurotrophic factor messenger RNA in the neurohypophysis. Thus, endogenous ciliary neurotrophic factor and leukemia inhibiting factor, produced by neurohypophyseal cells may function as a physiological survival factor for neurosecretory vasopressinergic neurons.
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PMID:Magnocellular vasopressinergic neurons in explant cultures are rescued from cell death by ciliary neurotrophic factor and leukemia inhibiting factor. 975 24


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