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PubMed1996

Regulation of signal transducer, GP13O and the LIF receptor in acute inflammation in vivo.

Recently we examined the expression of the IL-6 receptor (gp80) in three different models of acute inflammation [Geisterfer et al., 1993, Cytokine 5:1]. To continue these studies, we examined the mRNA expression of signal transducing molecule, gp130, and the LIF-R as associated members of a receptor family. Rats were treated with either Freund's complete adjuvant (FA) via intraperitoneal injection, LPS via intravenous injection, or turpentine via subcutaneous injection. The levels of gp130 and LIF-R mRNA expression had a maximum 2-3-fold increase over a 24 h period. However, the time of the maximum increase differed depending on the treatment the rats received. FA treated rats had a maximum induction of gp130 mRNA levels of 2.2-fold (for the 7.5 kb transcript) and 1.3-fold (for the 9.0 kb transcript) at 12 h. LPS treated rats had a maximum increase at 3 h where message levels increased 2.5-fold (7.5 kb) and 1.2-fold (9.0 kb). Turpentine-injected rats showed little difference in gp130 mRNA levels at any time after injection compared to controls. Maximum LIF-R mRNA levels also differed depending on the type of treatment the rats received. FA-injected rats showed a 2.1-fold mRNA increase at 3 h, whereas LPS treated rats show a maximum 2.4-fold increase at 18 h. Turpentine-injected rats showed little increase in mRNA levels compared to controls. Injection of purified recombinant rat IL-6 (rIL-6) had little effect on LIF-R mRNA levels, but had a dramatic inducing effect on gp130 mRNA levels. Rats were also injected (i.p.) with Dexamethasone (Dex) and this had no effect on either gp130 or LIF-R mRNA level expression. These in vivo results indicated that IL-6 has a major role in the regulation of its own receptors, IL-6R (gp80), and gp130, and the onset of acute phase response. We found that the maximum IL-6R (gp80), gp130 and LIF-R mRNA levels peaked at different times depending on the type of acute inflammation induced in the rat. It seems that various combinations of cytokines and hormones are released depending on the type of acute inflammation, and these in turn regulate the expression of diverse receptors on the hepatocyte, resulting in different acute phase kinetics in the various models of inflammation.

Acute Disease↗
PubMed1997

Regulation of interleukin 6 expression by cardiotrophin 1.

Cardiotrophin 1 (CT-1) is a recently described cytokine sharing many biological properties with those reported previously for leukaemia inhibitory factor (LIF). In the present study we show that CT-1 binds to the KB epidermoid cancer cell surface through a tripartite receptor complex which includes the gp130 signal transducing protein, LIF receptor beta (LIFR beta) and a third component displaying a molecular weight of 80 kDa. CT-1 activates gp130 and LIFR beta transducing components, as attested by analysing their tyrosine phosphorylation level. The activation process is relayed to the nucleus by the recruitment of the STAT3 transcription factor. Analysis of KB cell line culture supernatants after CT-1 treatment indicates that CT-1 stimulates the production of interleukin 6 (IL-6) in a time- and dose-dependent manner. This stimulation of IL-6 production by CT-1 is associated with an increase in intracellular levels of IL-6 mRNA. This study suggests that at least in some pathological situations CT-1 might represent an immunomodulator regulating cytokine-induced gene products.

Antigens, CD↗
PubMed1998

Modulation of cartilage proteoglycan metabolism by LIF binding protein.

Leukaemia inhibitory factor (LIF) and oncostatin M (OSM) exhibit pleiotropic biological activities, share many structural and genetic features and bind with high affinity to the same receptor (LIF/OSM receptor). A soluble form of the LIF-R alpha, called LIF binding protein (LBP) has been isolated from mouse serum. LIF and OSM stimulate proteoglycan (PG) release and inhibit PG synthesis in cultured pig articular cartilage explants. The aim of this study was to determine whether LBP can block PG resorption and or reverse the inhibition of PG synthesis induced by LIF and OSM. In cultured pig cartilage explants LBP was found to dose dependently inhibit LIF stimulated release of PGs and reverse the suppression of PG synthesis. LBP was found to substantially attenuate the effects of LIF. In contrast only partial inhibition of the stimulatory effect of OSM was observed at the highest concentration of LBP available. At maximal concentrations, LBP produced minimal reversal of OSM mediated inhibition of PG synthesis. When tested in combination LIF and OSM had no additive effects on PG metabolism, but the combination of LIF and IL-1 and also OSM and IL-1 did show additive effects in respect to stimulation of PG catabolism and inhibition of PG synthesis. These effects were significantly greater than those observed for LIF, OSM and IL-1 alone. The results suggest that pig articular chondrocytes possess the LIF/OSM receptor, but possibly not an independent OSM receptor. The actions of mLBP indicate that rhLBP could be a clinically useful antagonist for LIF and perhaps OSM.

Animals↗
PubMed1999

Presence of leukaemia inhibitory factor (LIF) and LIF-receptor chain (gp190) in osteoclast-like cells cultured from human giant cell tumour of bone. Ultrastructural distribution.

The behaviour of multinucleated giant cells (MNC) obtained from a giant cell tumour of the tibia and cultured on glass coverslips or on devitalized dentin slices was investigated using light and electron microscopy. Cells were studied in the presence or absence of LIF a cytokine known to be involved in bone turnover and to act as a growth factor in some solid tumours. The direct effect of LIF on MNC was examined by a post-embedding colloidal gold immunocytochemistry process using human anti-LIF and anti-LIF-receptor (chain gp190) antibodies. After 7 days of culture, the MNC obtained displayed osteoclast immunocytochemical features. Moreover, these MNC were able to resorb large amounts of dentin and presented typical features of active osteoclasts. Immunolocalization of LIF and LIF-receptor revealed the presence of this cytokine and its receptor within the cytoplasm and nucleus of active resorbing MNC. LIF upmodulated MNC number and nucleation but decreased their ability to resorb dentin. The present study suggests that MNC obtained from human GCT, currently considered as osteoclast-like cells, are targets for LIF and may be a source of LIF production in this pathological condition.

Bone Neoplasms↗
PubMed2000

Soluble glycoprotein 130 (gp130) attenuates OSM- and LIF-induced cartilage proteoglycan catabolism.

Oncostatin M (OSM) and leukaemia inhibitory factor (LIF) exhibit pleiotropic biological activities and share many structural and genetic features. The two cytokines bind with high affinity to the same receptor (LIF/OSM receptor), which consists of the LIF receptor alpha chain (LIFRalpha) and the signal transduction unit gp130. A soluble form of the beta chain of the receptor complex called soluble gp130 (sgp130) has been cloned. In this study, we sought to determine whether recombinant sgp130 or anti-gp130 Ab could attenuate the resorption of proteoglycans induced by OSM and LIF in articular cartilage explants. The results show that at high concentrations sgp130 is capable of attenuating both LIF and OSM mediated resorption. In contrast, anti-gp130 Ab selectively inhibited the stimulation of proteoglycan (PG) release by OSM, albeit minimally. The failure of anti-gp130 to attenuate LIF stimulated PG resorption may be due to the normal interaction of LIF with LIFRalpha and unfettered heterodimerization of LIFRalpha with gp130 in the presence of the antibody. The results indicate that sgp130 and anti-gp130 can modulate cartilage PG metabolism in vitro. Whether sgp130 may have therapeutic activity in models of arthritis or indeed in arthritic diseases remains to be determined.

Animals↗
PubMed1994

Leukemia inhibitory factor and neurotrophins support overlapping populations of rat nodose sensory neurons in culture.

Recent studies in this and other laboratories demonstrated that leukemia inhibitory factor (LIF) can regulate differentiation and survival of nerve growth factor (NGF)-dependent primary sensory neurons. To determine whether development of NGF-independent sensory neurons could be similarly regulated, the present study examined the effects of LIF and the related cytokine-like growth factor, ciliary neurotrophic factor (CNTF), on survival of rat nodose ganglion (NG) cells in culture. In addition, survival in LIF-treated cultures was compared in the presence and absence of the neurotrophins brain-derived neurotrophic factor (BDNF), NT-3, and NT-4, factors previously shown to target NG sensory neurons, to determine whether the cytokine-like factors and neurotrophins act on the same population of ganglion cells. Treatment of dissociate cultures of Embryonic Day (E) 16.5 NG with LIF or CNTF (10 ng/ml) resulted in a four- to fivefold increase in neuronal survival; the number of neurons supported by either factor represented approximately 50% of the total NG population. In contrast, less than 10% of newborn NG neurons survived in the presence of LIF or CNTF, suggesting a loss in responsiveness to these factors during fetal development in vivo. In cultures of E16.5 ganglia, BDNF, NT-3, or NT-4 alone each increased cell survival to varying degrees (BDNF > NT-4 = LIF > NT-3); NGF, on the other hand, had no effect. Combining LIF with BDNF, NT-3, or NT-4 had only partially additive effects on NG neuron number (LIF + BDNF, 36% greater than BDNF alone; LIF + NT-3, 21% greater than LIF alone; LIF + NT-4, 49% greater than NT-4 or LIF alone; P < 0.05), indicating that LIF and these neurotrophins support survival of overlapping subsets of NG neurons in culture. To begin defining whether NG neurons were capable of responding to CNTF and LIF in vivo, Northern blots were used to examine expression of mRNAs coding for CNTF and LIF receptor components (CNTFR alpha, gp130, and LIFR beta) in the intact ganglion. mRNAs for all three receptor components were present in both E16.5 and newborn ganglia, suggesting that LIF and CNTF receptors are expressed in the NG in vivo. Taken together, these data demonstrate that LIF and CNTF can support survival of NGF-independent sensory neurons in culture and indicate that cytokine-like growth factors may play a role in regulating visceral sensory development in vivo.

Animals↗
PubMed2003

Leukemia inhibitory factor induces apoptosis of the mammary epithelial cells and participates in mouse mammary gland involution.

Leukemia inhibitory factor (LIF) is a multifunctional glycoprotein that displays multiple biological activities in different cell types, but to date there has been no report on its expression in the normal mammary gland. In this study we found that LIF is expressed at low but detectable levels in postpubertal, adult virgin, and pregnant mouse mammary glands. However, LIF expression drops after parturition to become almost undetectable in lactating glands. Interestingly, LIF expression shows a steep increase shortly after weaning that is maintained for the following 3 days. During this period, known as the first stage of mammary gland involution, the lack of suckling induces local factors that cause extensive epithelial cell death. It has been shown that Stat3 is the main factor in signaling the initiation of apoptosis, but the mechanism of its activation remains unclear. Herein, we show that LIF expression in the gland is induced by milk stasis and not by the decrease of circulating lactogenic hormones after weaning. Implantation of LIF containing pellets in lactating glands results in a significant increase in epithelium apoptosis. In addition, this treatment also induces Stat3 phosphorylation. We conclude that LIF regulated expression in the mouse mammary gland may play a relevant role during the first stage of mammary gland involution. Our results also show that LIF-induced mammary epithelium apoptosis could be mediated, at least partially, by Stat3 activation.

Animals↗
PubMed1993

The leukemia inhibitory factor receptor (LIFR) gene is located within a cluster of cytokine receptor loci on mouse chromosome 15 and human chromosome 5p12-p13.

The leukemia inhibitory factor receptor (LIFR) gene was localized to human chromosome 5p12-p13 by somatic cell hybrid analysis. Interspecific backcross analysis revealed that the murine locus was on chromosome 15 in a region of homology with human chromosome 5p. In both human and mouse genomes, the LIFR locus was linked to the genes encoding the receptors for interleukin-7, prolactin, and growth hormone.

Animals↗
PubMed2002

The upper cytokine-binding module and the Ig-like domain of the leukaemia inhibitory factor (LIF) receptor are sufficient for a functional LIF receptor complex.

To elucidate the function of the two cytokine-binding modules (CBM) of the leukemia inhibitory factor receptor (LIFR), receptor chimeras of LIFR and the interleukin-6 receptor (IL-6R) were constructed. Either the NH(2)-terminal (chimera RILLIFdeltaI) or the COOH-terminal LIFR CBM (chimera RILLIFdeltaII) were replaced by the structurally related CBM of the IL-6R which does not bind LIF. Chimera RILLIFdeltaI is functionally inactive, whereas RILLIFdeltaII binds LIF and mediates signalling as efficiently as the wild-type LIFR. Deletion mutants of the LIFR revealed that both the NH(2)-terminal CBM and the Ig-like domain of the LIFR are involved in LIF binding, presumably via the LIF site III epitope. The main function of the COOH-terminal CBM of the LIFR is to position the NH(2)-terminal CBM and the Ig-like domain, so that these can bind to LIF. In analogy to a recently published model of the IL-6R complex, a model of the active LIFR complex is suggested which positions the COOH-terminal CBM at LIF site I and the NH(2)-terminal CBM and the Ig-like domain at site III. An additional contact is postulated between the Ig-like domain of gp130 and the NH(2)-terminal CBM of the LIFR.

Amino Acid Substitution↗
PubMed1999

Activation of Jak-Stat and MAPK2 pathways by oncostatin M leads to growth inhibition of human glioma cells.

Oncostatin M (OSM) is a cytokine of the IL-6 family that modulates the growth of various cell types, at least in vitro. We have recently described that OSM inhibits growth and changes cell morphology of human glioma cell lines. Although leukemia inhibitory factor (LIF) receptor components are also expressed by these cells, the response to LIF was significantly weaker compared to OSM. We have therefore analyzed the signal transduction pathways induced by these cytokines. While OSM induces a number of strong tyrosine phosphorylations, including Janus tyrosine kinases (Jak) and the signal transducer and activator of transcription (Stat) proteins, LIF induces only minor tyrosine phosphorylation of Tyk2 and Stat3. Specific activation of the tyrosine phosphatase SHP-2 as well as the mitogen-activated kinase 2 (MAPK2) was found in glioma cells upon OSM treatment. MAPK2 turns out to be a crucial mediator of the OSM effect in glioma cells since inhibition of MAPK activity by the Mek1 inhibitor PD98059 blocks the OSM-induced inhibition of DNA synthesis by about 70%.

Blotting, Western↗
PubMed2000

Postnatal profiles of myogenic regulatory factors and the receptors of TGF-beta 2, LIF and IGF-I in the gastrocnemius and rectus femoris muscles of dy mouse.

The dystrophin-deficient mdx mouse presents muscle fiber necrosis but active muscle regeneration, probably due to an extensive recruitment of myogenic regulatory factors (MRF), several growth factors and cytokines, and favorable interaction of satellite cells. In contrast, the laminin alpha 2 (merosin)-deficient dy mouse shows progressive muscle fiber necrosis and ineffective muscle regeneration. Using Western blot and immunohistochemical analyses, we investigated the adaptive changes in MRF, growth factors and cytokines and their receptors in the muscles of dy mice during postnatal growth. The relative volume of MyoD, myogenin and Myf-5 proteins was markedly lower in the gastrocnemius and rectus femoris muscles of dy mice. Transforming growth factor-beta 2, leukemia inhibitory factor (LIF) and basic fibroblast growth factor were not up-regulated in the muscles of dy mice. The levels of the LIF receptor and insulin-like growth factor-I receptor levels were markedly decreased in the muscles of dy mice during the entire postnatal period observed in this study. Therefore, unlike the situation in mdx mice, the milieu of regeneration following repetitive damage seems to be degraded in the muscles of dy mice.

Aging↗
PubMed2006

The migration of bone marrow-derived non-hematopoietic tissue-committed stem cells is regulated in an SDF-1-, HGF-, and LIF-dependent manner.

INTRODUCTION: Recently we identified in bone marrow (BM) by employing chemotactic isolation to SDF-1 gradient combined with real time RT-PCR analysis a mobile population of CXCR4+ BM mononuclear cells that express mRNA for various markers of early tissue-committed stem cells (TCSCs). In this study we evaluated whether TCSCs respond to other motomorphogens, such as hepatocyte growth factor (HGF) and leukemia inhibitory factor (LIF). MATERIALS AND METHODS: We again employed chemotactic isolation combined with real-time RT-PCR analysis to assess whether murine and human BM contain TCSCs that respond to HGF and LIF gradients. We also evaluated expressions of HGF and LIF in damaged organs. RESULTS: We noted that the number of TCSCs is highest in BM from young (1- to 2-month-old) mice and decreases in 1-year-old animals. Murine and human TCSCs 1) respond to HGF and LIF gradients in addition to an SDF-1 gradient, 2) reside in populations of BM-derived non-hematopoietic CD45-cells, and 3) are released (mobilized) from BM into the peripheral blood (PB) during tissue injury (e.g. after partial body irradiation). CONCLUSIONS: These findings further support our theory of the BM as a "hideout" for TCSCs and we suggest that their presence in BM tissue should be considered before experimental evidence is interpreted simply as transdifferentiation/plasticity of hematopoietic stem cells. Since we demonstrated that not only SDF-1, but also HGF and LIF are upregulated in damaged tissues, we postulate that CXCR4+ c-Met+ LIF-R+ TCSC could be mobilized from the BM into the PB, from which they are subsequently chemoattracted to damaged organs, where they play a role in tissue repair/regeneration.

Age Factors↗
PubMed2005

Expression and function of leukaemia inhibitory factor and its receptor in normal and regenerating rat pancreas.

AIMS/HYPOTHESIS: It was recently reported that culturing adult exocrine cells in the presence of epidermal growth factor and leukaemia inhibitory factor (LIF) resulted in their transdifferentiation into endocrine beta cells. The aim of this study was to examine the expression and function of LIF in the pancreas. MATERIALS AND METHODS: We studied the expression of LIF and its receptor components, LIF-receptor-beta and gp130, by immunohistochemistry, western blotting and RT-PCR in normal rat pancreas, pancreas with duct ligation-induced islet neogenesis, and in pancreatic cell cultures. Isolated duct fragments were cultured in the presence of LIF and a janus kinase 2 (JAK2) inhibitor. RESULTS: LIF was detected by immunohistochemistry, western blot and RT-PCR in the ducts of the normal pancreas. Both LIF-receptor-beta and gp130 were detected by RT-PCR in the pancreas. Immunostaining revealed gp130 exclusively in the ducts and centro-acinar cells. After duct ligation-induced tissue injury, upregulation of LIF and its receptor occurred in rat pancreas. Metaplastic exocrine cells also started to express LIF and this was increased after alloxan treatment. Signalling via LIF-receptor-beta/gp130 involves the JAK/signal transducer and activator of transcription (STAT) pathway. LIF induced increased activation of STAT3 in pancreatic cells. In isolated duct fragments, addition of LIF resulted in a significant increase in duct cell proliferation, while a specific inhibitor of the JAK/STAT signalling pathway inhibited proliferation. CONCLUSION/INTERPRETATION: Our observations show that LIF and its receptor are expressed in cells from pancreatic ducts. The cytokine plays a role in pancreatic physiology, controls duct cell proliferation and is involved in repair processes following pancreatic injury.

Animals↗
PubMedDate not supplied

In vivo phage display selection yields atherosclerotic plaque targeted peptides for imaging.

PURPOSE: Atherosclerosis is a leading cause of morbidity and mortality in the Western world, yet specific imaging agents to detect and map inflammatory plaques are still lacking. PROCEDURES: We used in vivo phage display to interrogate early atherosclerotic lesions present in ApoE-/- mice with the goal of identifying plaque-associated endothelial cell internalized affinity ligands. RESULTS: We identified 30 phage families with some of these families exhibiting homology to known atherosclerotic proteins, namely, leukemia inhibitory factor, transferrin, and VLA-4. VLA-4 homologous peptides [termed vascular cellular adhesion molecule-1 (VCAM-1) internalizing peptide-28 (VINP28)] bound to and were internalized by VCAM-1-expressing cells and were inhibited by soluble VCAM-1. In addition, a VINP28 modified multimodal nanoparticle showed high affinity for endothelial cells expressing VCAM-1 but low affinity for macrophages or smooth muscle cells. CONCLUSION: The identified peptides represent a set of probes to interrogate the cell surface repertoire and potentially allow early detection of atherosclerosis.

Affinity Labels↗
PubMed1993

Pregnancy associated increase in mRNA for soluble D-factor/LIF receptor in mouse liver.

We examined the distribution of mRNAs for differentiation-stimulating factor (D-factor)/leukemia inhibitory factor (LIF) receptor in various mouse tissues by Northern blotting. A mouse cDNA fragment encoding the D-factor receptor was prepared by the RT-PCR method using human cDNA sequences as primers. The smallest mRNA (3 kb) was present in the liver, but not detectable in other tissues examined. Larger mRNAs (5 and 10 kb) were present in the placenta and the M1 cells, and also detectable in the liver, kidney, heart, lung, brain and embryos. Expression of 3 kb mRNA in the liver increased during pregnancy, being 20 times the initial level on day 15. D-factor receptor cDNAs were isolated from a cDNA library prepared from the liver of a pregnant mouse. Most of the cDNA clones encoded a soluble receptor. A cDNA probe specific for the cellular receptor did not hybridize with 3 kb mRNA in the liver. These results suggest that 3 kb mRNA encodes a soluble D-factor receptor and that the liver is the primary site of synthesis of this soluble receptor.

Amino Acid Sequence↗
PubMed1994

The crystal structure and biological function of leukemia inhibitory factor: implications for receptor binding.

The structure of murine leukemia inhibitory factor (LIF) has been determined by X-ray crystallography at 2.0 A resolution. The main chain fold conforms to the four alpha-helix bundle topology previously observed for several members of the hematopoietic cytokine family. Of these, LIF shows closest structural homology to granulocyte colony-stimulating factor and growth hormone (GH). Sequence alignments for the functionally related molecules oncostatin M and ciliary neurotrophic factor, when mapped to the LIF structure, indicate regions of conserved surface character. Analysis of the biological function and receptor specificity of a series of human-mouse LIF chimeras implicate two regions of receptor interaction that are located in the fourth helix and the preceding loop. A model for receptor binding based on the structure of the GH ligand-receptor complex requires additional, novel features to account for these data.

Amino Acid Sequence↗
PubMed1994

Maintenance of the pluripotential phenotype of embryonic stem cells through direct activation of gp130 signalling pathways.

Propagation of the undifferentiated pluripotential phenotype of embryonic stem (ES) cells is dependent on the cytokine differentiation inhibiting activity/leukemia inhibitory factor (DIA/LIF). The DIA/LIF receptor complex is a heterodimer of DIA/LIF receptor (DIA/LIF-R) and gp130. The latter is also a component of the interleukin-6 (IL-6) receptor complex. We report that a combination of IL-6 and soluble IL-6 receptor (sIL-6R), which can induce homodimerisation of gp130 and activation of signalling processes, sustains self-renewal of pluripotential ES cells. Our findings indicate that the IL-6/sIL-6R complex acts on ES cells through gp130 alone, bypassing DIA/LIF-R, and therefore implicate gp130 as the key component in the signalling pathway responsible for stem cell renewal.

Amino Acid Sequence↗
PubMed1996

Complementary tissue-specific expression of LIF and LIF-receptor mRNAs in early mouse embryogenesis.

The maintenance of pluripotential embryonic stem (ES) cells is dependent on the cytokine LIF. This report documents the mRNA expression profiles of LIF and the two components of the LIF-receptor complex, LIF-R and gp130, during early mouse embryogenesis. These mRNAs were undetectable in 1- or 2-cell embryos, but all were present by the blastocyst stage. LIF transcripts were localised in the differentiated trophectoderm, and were absent from the pluripotential inner cell mass. In contrast, LIF-R mRNA was found in the inner cell mass but not in the trophectoderm. This complementary pattern of expression is suggestive of a paracrine coupling between stem cells and differentiated progeny at the earliest stage of mammalian development. After implantation, transcripts for all components were down-regulated in the embryo. High levels of LIF-R and gp130 mRNAs were observed in the deciduum, however. These dynamic, tissue-specific expression patterns are consistent with regulatory roles for LIF or related cytokines, both in the maintenance of pluripotency in the mouse embryo, and in development of the foeto-maternal interface.

Animals↗