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PubMed1996

Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop.

We have a previously reported that interleukin-10 (IL-10) is a potent but IL-6-unrelated growth factor for freshly explanted myeloma cells (Lu et al, Blood 85:2521, 1995). We have also shown that exogenous IL-10 supported the growth of XG-1 and XG-2 human myeloma cell lines (HMCL) through an IL-6-independent mechanism. (Lu et al, Blood 85:2521, 1995). Because the IL-10 receptor does not involve the gp 130 IL-6 transducer, we have attempted to elucidate the mechanisms of IL-10 action on myeloma cells. Our results indicate that the myeloma cell growth factor activity of IL-10 was abrogated by an antibody to the gp 130 IL-6 transducer, indicating that it was mediated through one of the gp 130-activating cytokines. We found that myeloma cells from XG-1 and XG-2 HMCL and from 5 of 6 patients' tumoral samples produced oncostatin M (OM) constitutively but failed to produce IL-6, IL-11 and leukemia-inhibitory factor (LIF). The autocrine OM was inactive in the absence of IL-10 due to lack of a functional OM receptor on myeloma cells. IL-10, by inducing the receptor for LIF (LIFR), produced a functional autocrine OM loop in XG-1 and XG-2 cells and in primary myeloma cells from 2 patients. We also found that some myeloma cell lines (XG-4, XG-6, and XG-7) an fresh myeloma cells from 3 of 6 patients produced an autocrine IL-10 and that these cells constitutively expressed LIFR. One HMCL (XG-7) produced IL-10, OM, and IL-6 an expressed LIFR. The XG-7 cells used OM and IL-6 as autocrine growth factors. We have previously shown that IL-10 could induce IL-11 receptor in myeloma cells and confer on them sensitivity to IL-11 (Lu et al, FEBS Lett 377:515, 1995). Taken together, these results show that IL-10 is a key cytokine for inducing the expression of LIFR and IL-11R and possibly another uncharacterized OM coreceptor on myeloma cells and that OM and IL-10 might be produced by myeloma cells. They also emphasize that all myeloma cell growth factors reported to data involve an activation of the gp130 IL-6 transducer.

Antigens, CD↗
PubMed1996

Role of leukemia inhibitory factor during mammalian development.

Leukemia inhibitory factor (LIF) is a cytokine that exhibits proliferative, survival and differentiation activities on a wide range of cell types. A role for LIF in embryonic development is suggested by: i) its ability to stimulate the proliferation of embryonic stem (ES) cells in vitro, while maintaining their totipotency and ii) by both its maternal and embryonic expression at the time of blastocyst implantation. Functional studies of LIF and its receptor during mouse embryogenesis have been performed using the techniques of targeted gene replacement and transgene expression in ES cells to produce transgenic mice bearing either loss- or gain-of-function mutations for LIF activity. Whereas, the phenotype observed in the LIF gain-of-function mutant mice supports a role for LIF in early embryogenesis, the loss-of-function phenotypes point to more specialized functions for LIF in development and further reveal the redundant feature of the LIF cytokine/receptor family.

Animals↗
PubMed1997

Influence of leukemia inhibitory factor (LIF) on the survival, proliferation and differentiation of human erythroid progenitor cells. In vitro studies under serum free conditions.

Different inflammatory cytokines are involved in the pathogenesis of the anemia of chronic disease (ACD), by inhibiting the proliferation of erythroid progenitors. Leukemia inhibitory factor (LIF), is an important inflammatory cytokine, and the purpose of this study was to evaluate its effect on the proliferation and viability of human erythroid progenitors. We have found that LIF slightly increased the survival of human early progenitor cells cultured under serum free conditions. LIF also slightly costimulated in vitro growth of human erythroid colonies. This last effect seems to be a direct one, because we found that LIF receptor (LIF-R) is expressed in cells isolated from growing in vitro human erythroid BFU-E colonies. These data, and the data reported by others in in vivo models, where LIF administration to experimental animals did not change the values of erythropoietic parameters, demonstrate that this inflammatory cytokine itself is not involved in the pathogenesis of ACD.

Antigens, CD34↗
PubMed1997

Oncostatin M-specific receptor mediates inhibition of breast cancer cell growth and down-regulation of the c-myc proto-oncogene.

Human oncostatin M (OM) is a M(r) 28,000 glycoprotein that has been shown to regulate cell proliferation and differentiation. The biological activities of OM can be mediated by two different heterodimeric receptor complexes, the leukemia inhibitory factor (LIF)/OM shared receptor and the OM-specific receptor. In this study, we have examined the growth-regulatory effect of OM on 10 breast cancer cell lines derived from human tumors. The cellular proliferation of seven of these breast cancer cell lines was inhibited by OM. The three cell lines that did not respond to OM treatment lacked the expression of OM receptors. The growth-inhibitory activity of OM is examined further in the H3922 breast cancer cell line, which expresses the high-affinity OM receptor at a relatively higher level. We found that the cellular proliferation of H3922 cells was induced strongly by extrogenous epidermal growth factor (EGF), EGF-like factor, and basic fibroblast growth factor. The proliferative activities of these growth factors can be abolished totally by cotreatment of H3922 cells with OM. Treatment of H3922 cells with OM for 24 h did not block EGF binding or the induction of EGF receptor tyrosine phosphorylation. This finding suggests that OM interferes with the mitogenic signal at steps distal to the EGF receptor. Examination of proto-oncogene expression demonstrated that OM down-regulates the c-myc gene in H3922 cells. The biological effects reported herein are not shared by the OM-related cytokines interleukin 6 or LIF, as demonstrated by the inability of these proteins to inhibit cell growth or modulate c-myc gene expression in breast cancer cells. Additionally, the high-affinity binding of labeled OM cannot be displaced by LIF. Together, these data suggest that OM is a growth inhibitor for breast cancer cells. The inhibitory activity is mediated predominantly through the OM-specific receptor, and activation of this receptor abrogates growth factor stimulation and down-regulates the c-myc proto-oncogene.

Antineoplastic Agents↗
PubMed1997

Leukemia inhibitory factor (LIF) binding protein attenuates the phlogistic and abolishes the chondral effects of LIF in goat joints.

OBJECTIVE: To investigate the ability of murine leukemia inhibitory factor (LIF) binding protein (mLBP) to attenuate the effects of recombinant human LIF (rhLIF) in goat radiocarpal joints in vivo. METHODS: Endotoxin-free saline (1 ml) containing either 0.5 or 1 microg of rhLIF was injected into the left and right radiocarpal joints of male angora goats. One hour later the right radiocarpal joints were injected with either 1 or 5 microg of naturally occurring mLBP in 1 ml saline, while the left radiocarpal joints (controls) received 1 ml saline vehicle alone. Goat joints were examined for clinical features of inflammation and synovial fluid (SF) was aspirated on Day 0 (before injection) and Days 2 and 6 postinjection. Leukocyte counts and concentrations of keratan sulfate were determined in the SF. Proteoglycan synthesis and proteoglycan content of cartilage was determined ex vivo in cartilage explants obtained at Day 6. RESULTS: Preliminary time course studies in vitro showed that mLBP had to be added to cartilage explant cultures within 1 h of rhLIF for effective antagonism to occur. In joints injected with either 0.5 or 1 microg rhLIF significant increases in swelling, effusion volume, leukocyte counts, and SF keratan sulfate concentrations were observed relative to controls. Statistically significant depressions of ex vivo proteoglycan synthesis and in proteoglycan content of articular cartilage were also observed relative to controls. In joints injected with 1 microg rhLIF followed by 1 microg mLBP, statistically significant improvement was only observed in the rate of ex vivo cartilage proteoglycan synthesis. The observed rate did not differ significantly from that obtained in joints treated with vehicle alone. In contrast, in joints injected with 0.5 microg rhLIF followed by 5 microg mLBP, statistically significant improvement was observed in all variables. Treatment with 5 microg mLBP effectively negated the effects of rhLIF on joint swelling, effusion volume, leukocyte infiltration, and cartilage proteoglycan catabolism. CONCLUSION: Murine LBP has the ability to attenuate the phlogistic effects of rhLIF in radiocarpal joints of goats and also abolishes the stimulatory effect of rhLIF on cartilage proteoglycan catabolism and depression of ex vivo proteoglycan synthesis. These antiinflammatory and chondral effects suggest that a humanized derivative of mLBP could be a clinically useful antagonist for LIF in inflammatory diseases.

Animals↗
PubMed2005

Interleukin-11, IL-11 receptoralpha and leukemia inhibitory factor are dysregulated in endometrium of infertile women with endometriosis during the implantation window.

Interleukin (IL)-11 is essential for embryo implantation in the mouse and evidence suggests it has a role in implantation in humans. This study has evaluated immunoreactive IL-11, IL-11 receptor (R) alpha and leukemia inhibitory factor (LIF) in endometrium of infertile women with endometriosis (I/E) and normal fertile women (controls) during the implantation window. Endometrial biopsies from I/E (N = 7) were timed from the LH surge and were post-ovulatory days (POD) 5-10. Control biopsies (N = 8) from women were between days 19 and 24 of the menstrual cycle. Staining intensity of IL-11, IL-11Ralpha and LIF evaluated using semi-quantitative immunohistochemistry scores. Immunoreactive IL-11, IL-11Ralpha and LIF were present predominantly in glandular epithelium, while luminal epithelium showed patchy staining. All controls stained positively for IL-11, IL-11Ralpha and LIF in glandular epithelium. IL-11 and IL-11Ralpha staining was absent from glandular epithelium in cohorts of I/E. LIF staining intensity in glandular epithelium was significantly lower in I/E compared to controls. The results suggest that reduced endometrial IL-11 and/or LIF may contribute to infertility in some endometriotic women.

Adult↗
PubMed2006

Evidence for functional inter-relationships between FOXP3, leukaemia inhibitory factor, and axotrophin/MARCH-7 in transplantation tolerance.

In an ex vivo mouse model, regulatory transplantation tolerance is not only linked to Foxp3, but also to release of leukaemia inhibitory factor (LIF) and to expression of axotrophin (also known as MARCH-7), a putative ubiquitin E3 ligase associated with feedback control of T cell activation and of T cell-derived LIF. Given this coordinate correlation with tolerance, we now ask if Foxp3 expression is influenced by LIF or by axotrophin. In spleen cells from allo-rejected mice we found that exogenous LIF reduced interferon gamma release in response to donor antigen by 50%, but LIF had no direct effect on levels of Foxp3 protein in allo-primed cells that were either tolerant, or aggressive, for donor antigen. However, we did find an effect of axotrophin on Foxp3: in the axotrophin null mouse, thymic Foxp3 transcripts were reduced compared to axotrophin wildtype littermates. To test whether these findings in the mouse were of potential significance in man we measured transcript levels of axotrophin and LIF in peripheral blood cell samples collected for a recently published clinical study concerning haematopoietic stem cell recipients. In controls, human peripheral blood CD4+CD25+cells contained significantly more FOXP3 and axotrophin than CD4+CD25-cells. In bone marrow autograft recipients, where peripheral blood cell samples directly represent both the grafted tissue and the immune response, both FOXP3 and axotrophin negatively correlated with graft versus host disease (GVHD). These data suggest that (i) thymic Foxp3+T cell development is influenced by axotrophin; and (ii) clinical auto-GVHD inversely correlates with axotrophin transcript expression as has been previously reported for FOXP3.

Animals↗
PubMed2000

Temporal expression of mRNAs for neuropoietic cytokines, interleukin-11 (IL-11), oncostatin M (OSM), cardiotrophin-1 (CT-1) and their receptors (IL-11Ralpha and OSMRbeta) in peripheral nerve injury.

The mRNA expression pattern of the neuropoietic cytokines, interleukin-11 (IL-11), oncostatin M (OSM) and cardiotrophin-1 (CT-1), and their receptor components (IL-11Ralpha and OSMRbeta) was examined in peripheral nerves on two different types of injury, crush and transection. The IL-11 mRNA increased after nerve damage and immediately returned to control levels. The OSM mRNA expression increased rapidly after nerve injury and relatively high expressions were maintained for at least 14 days. The CT-1 mRNA was not expressed in any time before and after the injury. Interestingly, IL-11Ralpha was expressed in the intact nerve and decreased after injury. The expression of OSMRbeta increased slightly after the injury. Moreover, temporal mRNA expression pattern of these neuropoietic cytokines and receptors was similar between the crushed and transected models. Each neuropoietic cytokine of IL-11, OSM and CT-1 has its own specific temporal mRNA expression pattern, which is also different from those of ciliary neuro-trophic factor (CNTF), leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). These results suggest that all neuropoietic cytokines have distinctive functions in nerve degeneration and repair process in response to peripheral nerve injury.

Animals↗
PubMed2001

Genes involved in implantation.

The endometrium is normally a hostile environment for an embryo, except for a short phase in each reproductive cycle known as the 'window of receptivity'. The precise molecular events involved in this transformation are not well understood. Application of state-of-the-art techniques of the 1990s has identified some of the genes involved, which are reviewed here. Mice with a null mutation in either the gene for leukemia inhibitory factor or the interleukin-11 receptor alpha chain are infertile, owing in both cases to a failure of embryo implantation. Both of these genes are expressed in the human endometrium with patterns suggesting a role in human fertility. The technique of RNA differential display has been applied to a comparison of the expression of genes at implantation sites v. inter-implantation sites in the mouse uterus on the first day of implantation, and has defined additional genes whose products may be important for this process. Among these are the calcium-binding protein D9K, the monoclonal non-specific suppressor factor beta, and the splicing factor SC35. The major challenge is to determine whether manipulation of such genes can increase or decrease endometrial receptivity in humans.

Animals↗
PubMed2000

The ciliary neurotrophic factor and its receptor, CNTFR alpha.

Ciliary neurotrophic factor (CNTF) is expressed in glial cells within the central and peripheral nervous systems. CNTF stimulates gene expression, cell survival or differentiation in a variety of neuronal cell types such as sensory, sympathetic, ciliary and motor neurons. In addition, effects of CNTF on oligodendrocytes as well as denervated and intact skeletal muscle have been documented. CNTF itself lacks a classical signal peptide sequence of a secreted protein, but is thought to convey its cytoprotective effects after release from adult glial cells by some mechanism induced by injury. Interestingly, mice that are homozygous for an inactivated CNTF gene develop normally and initially thrive. Only later in adulthood do they exhibit a mild loss of motor neurons with resulting muscle weakness, leading to the suggestion that CNTF is not essential for neural development, but instead acts in response to injury or other stresses. The CNTF receptor complex is most closely related to, and shares subunits with the receptor complexes for interleukin-6 and leukemia inhibitory factor. The specificity conferring alpha subunit of the CNTF complex (CNTFR alpha), is extremely well conserved across species, and has a distribution localized predominantly to the nervous system and skeletal muscle. CNTFR alpha lacks a conventional transmembrane domain and is thought to be anchored to the cell membrane by a glycosyl-phosphatidylinositol linkage. Mice lacking CNTFR alpha die perinatally, perhaps indicating the existence of a second developmentally important CNTF-like ligand. Signal transduction by CNTF requires that it bind first to CNTFR alpha, permitting the recruitment of gp130 and LIFR beta, forming a tripartite receptor complex. CNTF-induced heterodimerization of the beta receptor subunits leads to tyrosine phosphorylation (through constitutively associated JAKs), and the activated receptor provides docking sites for SH2-containing signaling molecules, such as STAT proteins. Activated STATs dimerize and translocate to the nucleus to bind specific DNA sequences, resulting in enhanced transcription of responsive genes. The neuroprotective effects of CNTF have been demonstrated in a number of in vitro cell models as well as in vivo in mutant mouse strains which exhibit motor neuron degeneration. Intracerebral administration of CNTF and CNTF analogs has also been shown to protect striatal output neurons in rodent and primate models of Huntington's disease. Treatment of humans and animals with CNTF is also known to induce weight loss characterized by a preferential loss of body fat. When administered systemically, CNTF activates downstream signaling molecules such as STAT-3 in areas of the hypothalamus which regulate food intake. In addition to its neuronal actions, CNTF and analogs have been shown to act on non-neuronal cells such as glia, hepatocytes, skeletal muscle, embryonic stem cells and bone marrow stromal cells.

Animals↗
PubMed2001

Cloning of rat interleukin 11 and interleukin 11 receptor alpha chain and analysis of their expression in rat uterus in the peri-implantation period.

Studies in mice have shown that interleukin 11 (IL-11) signalling is required for female fertility. In the absence of IL-11, decidualization is markedly retarded and implantation fails. IL-11 acts via a heterodimeric receptor composed of a ligand-specific receptor alpha chain (IL-11R alpha) and the signalling moiety gp130. This study reports the cloning of genes encoding rat IL-11 and IL-11R alpha. RNase protection was used to demonstrate that expression of IL-11 is upregulated in the rat uterus at the initiation of implantation at 5.5 days after mating. Expression of the genes encoding the two receptor components, IL11Ra and gp130, did not change throughout the peri-implantation period. In situ hybridization studies revealed that, as in mice, expression of IL-11 was high in the primary decidual zone at the time of the attachment reaction, whereas IL11Ra was expressed throughout primary and secondary decidua. Conservation of the temporal and spatial expression of IL-11 and IL-11R alpha in the uterus of the mouse and rat during the peri-implantation period will facilitate future studies investigating the role of IL-11 in fertility.

Amino Acid Sequence↗
PubMed1996

Alanine substitution for Thr268 and Asp269 of soluble ciliary neurotrophic factor (CNTF) receptor alpha component defines a specific antagonist for the CNTF response.

Ciliary neurotrophic factor (CNTF) associates with an alpha subunit (CNTFRalpha) of the receptor complex to initiate signal transduction by facilitating heterodimerization of the gp130 transducing protein and the leukemia inhibitory factor receptor (LIFR) beta. CNTFRalpha is anchored to the membrane by a glycosylphosphatidylinositol linkage; however, a soluble form of the alpha subunit can still bind CNTF to recruit the signal transducing components of the receptor complex. In the present study we show that alanine substitution for residues Thr268 and Asp269 of the CNTFRalpha subunit results in a mutated receptor subunit (R3), which can bind CNTF with an affinity similar to that of the wild type CNTFRalpha but, when expressed as a soluble receptor subunit, lowers the binding of CNTF to its tripartite receptor. In addition, CNTFR3alpha inhibits the proliferation of the TF1 hematopoietic cell line triggered by CNTF plus soluble wild type CNTFRalpha but not by IL-6 or oncostatin M. Similarly, CNTFR3alpha specifically antagonizes the induction of gp130 and LIFRbeta tyrosine phosphorylation observed in response to CNTF and wild type soluble CNTFRalpha in the HepG2 hepatoma cell line, as well as the subsequent events leading to haptoglobin synthesis. Positions 268 and 269 of CNTFRalpha appear to be critical for its interaction with gp130 and LIFRbeta, whereby alanine substitution of the residues at these positions results in antagonism of the CNTF-induced response.

Alanine↗
PubMed1996

The human interleukin-11 receptor alpha gene (IL11RA): genomic organization and chromosome mapping.

The high-affinity receptor for interleukin-11 (IL-11) is composed of two subunits, IL-11 receptor alpha chain (IL-11R alpha) and gp130, the common subunit of the interleukin-6 (IL-6), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor, and oncostatin M receptors. The IL-11 receptor-specific alpha chain shares homologies with the alpha chain of the CNTF and IL-6 receptors. We isolated and characterized genomic DNA clones encompassing the entire coding sequence of the IL-11R alpha cDNA. The exon-intron organization of the IL-11R gene (HGMW-approved symbol IL11RA) is consistent with the predicted structure of the different domains of the IL-11R alpha protein, confirming evolutionary conservation at the level of gene organization among the hematopoietic cytokine receptor family. The IL-11R gene has been assigned to chromosome 9 band p13 by in situ hybridization using human IL-11R alpha cDNA as a probe. The fact that the ciliary neurotrophic factor (CNTFR) gene has recently been localized on this same band and the conserved genomic structure between IL-11R and CNTFR suggest that they may have evolved from a common ancestor.

Base Sequence↗
PubMed1993

Oncostatin-M stimulates tyrosine protein phosphorylation in parallel with the activation of p42MAPK/ERK-2 in Kaposi's cells. Evidence that this pathway is important in Kaposi cell growth.

Oncostatin-M (OSM) is a potent mitogen for Kaposi's sarcoma (KS) cells. We studied signaling by the OSM receptor in three AIDS-related KS lines and show induction of tyrosine phosphorylation of 145-, 120-, 85-, and 42-kD substrates. The 42-kD substrate was identified as p42MAPK (mitogen-activated protein kinase), also known as ERK-2. This serine/threonine kinase relays mitogenic signals from receptor tyrosine protein kinases (TPKs) or receptor-associated TPKs to transcriptional activators. The OSM dose dependence for MAP kinase activation and induction of KS cell growth were almost identical, suggesting functional linkage. MAP kinase activation was dependent on tyrosine phosphorylation, and both OSM-induced MAP kinase activity and KS cell growth could be suppressed by TPK inhibitors, genistein and geldanomycin. OSM also stimulated tyrosine phosphorylation of similar substrates and MAP kinase activity in human vein endothelial cells. While it has been proposed that the OSM receptor may include the gp130 subunit of the IL-6 receptor and alpha-chain of leukemia inhibitory factor (LIF) receptor, neither LIF nor r.IL-6 induced tyrosine protein phosphorylation or p42MAPK activation in KS cells. However, r.IL-6 did stimulate tyrosine phosphorylation and p42MAPK activity in the human B cell line, AF-10, while OSM and LIF exerted no effects. Our results indicate that, although the OSM and IL-6 receptors share a common signaling pathway, this pathway is selectively activated by OSM in Kaposi's cells.

Acquired Immunodeficiency Syndrome↗
PubMed1995

CNTF variants with increased biological potency and receptor selectivity define a functional site of receptor interaction.

Human CNTF is a neurocytokine that elicits potent neurotrophic effects by activating a receptor complex composed of the ligand-specific alpha-receptor subunit (CNTFR alpha) and two signal transducing proteins, which together constitute a receptor for leukemia inhibitory factor (LIFR). At high concentrations, CNTF can also activate the LIFR and possibly other cross-reactive cytokine receptors in the absence of CNTFR alpha. To gain a better understanding of its structure-function relationships and to develop analogs with increased receptor specificity, the cytokine was submitted to affinity maturation using phage display technology. Variants with greatly increased CNTFR alpha affinity were selected from a phage-displayed library of CNTF variants carrying random amino acid substitutions in the putative D helix. Selected variants contained substitutions of the wild-type Gln167 residue, either alone or in combination with neighboring mutations. These results provide evidence for an important functional role of the mutagenized region in CNTFR alpha binding. Affinity enhancing mutations conferred to CNTF increased potency to trigger biological effects mediated by CNTFR alpha and enhanced neurotrophic activity on chicken ciliary neurons. In contrast, the same mutations did not potentiate the CNTFR alpha-independent receptor actions of CNTF. These CNTF analogs thus represent receptor-specific superagonists, which should help to elucidate the mechanisms underlying the pleiotropic actions of the neurocytokine.

Amino Acid Sequence↗
PubMed1999

Activation of the signal transducer glycoprotein 130 by both IL-6 and IL-11 requires two distinct binding epitopes.

The coordination and regulation of immune responses are primarily mediated by cytokines that bind to specific cell surface receptors. Glycoprotein 130 (gp130) belongs to the family of class I cytokine receptors and is the common signal-transducing receptor subunit shared by the so-called IL-6 type cytokines (IL-6, IL-11, ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin M, and cardiotrophin-1). The inflammatory cytokines IL-6 and IL-11 induce gp130 homodimerization after binding to their specific alpha receptors, which leads to the activation of the Janus kinase/STAT signal transduction pathway. A molecular model of IL-6/IL-6R/gp130, which is based on the structure of the growth hormone/growth hormone receptor complex, allowed the selection of several amino acids located in the cytokine-binding module of gp130 for mutagenesis. The mutants were analyzed with regard to IL-6- or IL-11-induced STAT activation and ligand binding. It was found that Y190 and F191 are essential for the interaction of gp130 with IL-6 as well as IL-11, suggesting a common mode of recognition of helical cytokines by class I cytokine receptors. Furthermore, the requirement of the gp130 N-terminal Ig-like domain for ligand binding and signal transduction was demonstrated by the use of deletion mutants. Thus, besides the observed analogy to the growth hormone/growth hormone receptor complex, there is a substantial difference in the mechanism of receptor engagement by cytokines that signal via gp130.

Animals↗