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PubMed1997

Leukemia inhibitory factor induces the 85-kDa cytosolic phospholipase A2 gene expression in cultured human bronchial epithelial cells.

Leukemia inhibitory factor (LIF) has become increasingly recognized as an important regulator of inflammation. This study is designed to determine whether LIF has an effect on arachidonate metabolism in human airway epithelial cells. LIF (100 ng/ml) induced a significantly increased release of prelabeled [3H] arachidonic acid (AA) from the human bronchial epithelial cell line (BEAS 2B cell) as well as from the primary cultures of human bronchial epithelial cells. Exposure of the LIF stimulated BEAS 2B cells to calcium ionophore A23187 (10(-5) M, 15 min) caused a further increase of [3H]AA release. To identify the role of cytosolic phospholipase A2 (cPLA2) in this upregulation of AA release, further experiments were performed to determine the expression of cPLA2 in the BEAS 2B cells. Immunoblot analysis indicated that LIF increased cPLA2 protein expression. Ribonuclease protection assay showed that LIF induced an increase of cPLA2 mRNA levels following 3 h to 24 h treatment. Nuclear run-on experiments suggested that LIF upregulated cPLA2 gene expression through post-translational regulation. These results demonstrate that LIF induces cPLA2 gene expression and modulates arachidonate metabolism in airway epithelial cells.

Arachidonic Acid↗
PubMed2003

Expression of cytokines and cytokine receptors in the rat brain after kainic acid-induced seizures.

We have previously shown that IL-6 protein levels are increased in cerebrospinal fluid in humans after recent tonic-clonic seizures with unchanged levels of IL-1beta and TNFalpha. Here we studied the expression of cytokines IL-6, LIF, IL-1beta and TNFalpha and cytokine receptors IL-6R, LIFR and Gp130 in the rat brain after kainic acid-induced status epilepticus using Northern blot analysis and in situ hybridization histochemistry. After seizures, IL-6 mRNA was induced in the hippocampus, cortex, amygdala and meninges, and IL-6R was up-regulated in the hippocampus. LIF was up-regulated in the hippocampus, cortex and meninges after seizures, and LIFR mRNA was induced in the hippocampus and cortex. Gp130 was constitutively expressed in the brain. After seizures, Gp130 transcription was rapidly induced in the meninges. In thalamus, cortex, amygdala and hippocampus Gp130 mRNA was induced in a delayed fashion. IL-1beta transcription was induced in the temporal lobe cortex and thalamus, and TNFalpha in the hippocampus. In general, the cytokine and their receptor mRNA levels were low in intact rat brain, but were induced by seizures. Since IL-6 and LIF transcripts were induced in the meninges after seizures, the protein products of these transcripts may be more readily released in cerebrospinal fluid after seizures. In addition, the activity of IL-6 and LIF signaling pathways may be influenced by increased expression of their receptors after seizures.

Animals↗
PubMed1997

Cytokines which signal through the LIF receptor and their actions in the nervous system.

A number of different cytokines, each initially characterized on the basis of very different biological activities, all have very similar signalling pathways and share a similar tertiary structure. These cytokines include leukaemia inhibitory factor, ciliary neuronotrophic factor, oncostatin M, growth-promoting activity and cardiotrophin 1. They all have been found to regulate a number of properties of cells of the developing and mature nervous system in vitro and thus are neuroregulatory cytokines. The actions of these cytokines include regulation of neurotransmitter phenotype, differentiation of neuronal precursor cells both in the peripheral nervous system and in the spinal cord, survival of differentiated neurons, and regulation of development of both astrocytes and oligodendrocytes. In addition, studies in animal models show that these factors can rescue sensory and motor neurons from axotomy-induced cell death, which suggests that they can act as trauma factors for injured neurons. Analysis of the expression patterns of the different neuroregulatory cytokines and their receptors reveals that the receptors are expressed throughout nervous system development and following trauma, whereas the cytokines show temporal and spatial specific expression patterns. This is consistent with the idea that specific cytokines have specific roles in neural development and repair, but that their signalling pathways are shared. The phenotypes of the receptor knockouts show clear deficits in nervous system development, indicating a crucial role for LIF receptor signalling. Knockouts of individual cytokines are less dramatic, but LIF and CNTF knockouts do reveal deficits in maintenance of motor neurons or following trauma. Thus, whereas LIF and CNTF have clear roles in maintenance and following trauma, it is unclear which of the cytokines is involved in nervous system development. In clinical terms, these findings add further support to the use of these cytokines in nervous system trauma and disease.

Animals↗
PubMed2000

Expression of leukemia inhibitory factor (LIF) and LIF receptor (LIF-R) in the human adrenal cortex: implications for steroidogenesis.

It is well established that steroidogenesis in the adrenal cortex is regulated by extraadrenal factors, such as ACTH and angiotensin II. However, over the last years, it has become increasingly clear that paracrine and autocrine mechanisms are also important for steroid synthesis in the adrenal gland. The current study was designed to analyze whether the pleiotropic cytokine leukemia inhibitory factor (LIF) and/or its receptor (LIF-R) are expressed in the normal human adrenal cortex, and whether they may play a role in regulating steroidogenesis. Using LIF- and LIF-R-specific primers, we show by RT-PCR that both mRNAs are expressed in this tissue, as well as in the NCI-H295 adrenal carcinoma cell line. The correct sequences of the PCR products were verified by restriction enzyme analysis and DNA sequencing. Immunohistochemistry, employing specific antibodies against LIF and LIF-R, reveals expression of both proteins in the normal human adrenal cortex. Finally, we show that LIF can significantly enhance basal and ACTH-induced production of cortisol and aldosterone in NCI-H295 cells. In summary, we show for the first time that LIF and its receptor are expressed in the normal human adrenal cortex. Our stimulation experiments indicate that the intraadrenal LIF/LIF-R system may participate in regulating adrenal steroidogenesis.

Adrenal Cortex↗
PubMed2000

Expression of leukemia inhibitory factor receptor mRNA in sensory dorsal root ganglion and spinal motor neurons of the neonatal rat.

Previous studies have shown that the application of leukemia inhibitory factor to the proximal nerve stump prevents the degeneration of axotomized sensory neurons in the dorsal root ganglion and motor neurons in the spinal cord of newborn rats. This study investigated the expression of leukemia inhibitory factor receptor mRNA in these neurons using in situ hybridization. Leukemia inhibitory factor receptor mRNA was detected both in sensory neurons within the dorsal root ganglion and motor neurons of the cervical spinal cord. Twenty-four hours after axotomy these neurons continue to express leukemia inhibitory factor receptor mRNA. This pattern of leukemia inhibitory factor receptor expression provides a mechanism by which endogenous and exogenous leukemia inhibitory factor could act on injured sensory and motor neurons.

Animals↗
PubMed2001

Leukemia inhibitory factor induces nociceptin mRNA in cultured rat cortical neurons.

The effects of leukemia inhibitory factor (LIF) on the expression of neurotransmitter synthetase and neuropeptide mRNAs in cultured rat cortical neurons were examined by reverse transcription-polymerase chain reaction. Nociceptin mRNA expression was increased by treatment with 20 or 80 ng/ml LIF for 24 h, but choline acetyl transferase, glutamic acid decarboxylase, enkephalin, dynorphin, substance P, somatostatin and galanin mRNA expression were not altered by LIF. These observations indicated a specific effect of LIF on nociceptin gene regulation in cultured cortical neurons.

Aging↗
PubMed2000

Expression of interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 in the murine cerebellum and neuropathological effect of leukemia inhibitory factor on cerebellar Purkinje cells.

Expression of glycoprotein 130 and the related receptors, including interleukin-6 receptor and leukemia inhibitory factor receptor, was examined in the murine cerebellum at the protein level. Western blot analysis revealed that interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 were expressed in the murine cerebellum. Immunoreactivities for interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 were strongly localized on the cell body of Purkinje cells, indicating that both interleukin-6 and leukemia inhibitory factor could act directly on Purkinje cells in murine adult mice. The expressions of interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 were observed on the cell membranes of Purkinje cells by immunoelectron microscopy. Immunoreactivity for the interleukin-6 receptor was also detected in the cytoplasm of Purkinje cells. Injection of a murine hemopoietic cell line, FDC-P1 cells, transfected with the complementary DNA encoding the leukemia inhibitory factor led to a reduction in calbindin-positive dendrites of the Purkinje cells.The present results suggest that the leukemia inhibitory factor affects cerebellar functions through Purkinje cells.

Animals↗
PubMed2002

Inflammation induces serine protease inhibitor 3 expression in the rat pineal gland.

In the rat pineal gland, prominent expression of serine protease inhibitor 3 (SPI-3) mRNA is seen after systemic injection of lipopolysaccharide. The up-regulation of SPI-3 mRNA expression is also confirmed by northern blotting. Most SPI-3 mRNA-positive cells simultaneously express synaptophysin, a marker for pinealocytes, but not glial fibrillary acidic protein, a marker for astrocytes. This indicates that SPI-3 mRNA-positive cells are pinealocytes. Almost all SPI-3 mRNA-positive cells also showed translocation of the signal transducers and activators of transcription 3 (STAT3) into nuclei after lipopolysaccharide injection. These data support previous in vitro results that SPI-3 expression is induced in a STAT3-mediated manner. In addition, the expression of ciliary neurotrophic factor receptor (CNTFR) and leukemia inhibitory factor receptor (LIFR) mRNAs, but not of interleukin 6 receptor mRNA, was up-regulated after systemic lipopolysaccharide treatment. Because these receptors are upstream of STAT3, the present results suggest that cytokines such as LIF and/or CNTF induce SPI-3 expression via STAT3 in the pineal gland in response to inflammatory stimulus. We conclude that although the functional consequences of SPI-3 in the pineal gland during systemic inflammation are unknown, SPI-3 may have a crucial role in preventing some degenerative proteolysis induced by inflammatory stimuli.

Acute-Phase Proteins↗
PubMed2000

Immune activation in the early puerperium is related to postpartum anxiety and depressive symptoms.

The pathophysiology of the postpartum blues, common transient mood disorders in the first week postpartum, has remained elusive. Recently, however, it has been shown that depression and anxiety disorders are accompanied by activation of the inflammatory response system (IRS). This study was developed to determine whether the postnatal blues is associated with IRS activation. Serum concentrations of interleukin-6 (IL-6), IL-6 receptor (IL-6R), gp130 (the IL-6 signaling protein), IL-1R antagonist (IL-1RA) and leukemia inhibitory factor receptor (LIFR) were assayed in 22 nonpregnant women and in 91 pregnant women before delivery and 1 and 3 days after delivery. On each occasion the parturient women completed the State version of the Spielberger State-Trait-Anxiety-Inventory (STAI) and the Zung Depression Rating Scale (ZDS). Serum IL-6, IL-1RA and LIFR were significantly higher in pregnant women at the end of term than in nonpregnant women.

Adult↗
PubMed2002

Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor.

There is now evidence that schizophrenia may be accompanied by an activation of the monocytic and T-helper-2 (Th-2) arms of cell-mediated immunity (CMI) and by various alterations in the Th-1 arm of CMI. There is also evidence that repeated administration of typical and atypical antipsychotics may result in negative immunomodulatory effects. This study was carried out to examine (1) the serum concentrations of interleukin-8 (IL-8), IL-10, the soluble CD8 (sCD8) and the leukemia inhibitory factor receptor (LIF-R) in nonresponders to treatment with typical neuroleptics as compared with normal volunteers and responders to treatment; and (2) the effects of atypical antipsychotics on the above immune variables. The latter were determined in 17 nonresponders to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. The nonresponders had repeated measurements of the immune variables before, and 2 and 4 months after treatment with clozapine or risperidone. Serum IL-8 and IL-10 were significantly higher in schizophrenic patients than in normal controls. The serum concentrations of the sCD8 were significantly increased 2 months, but not 4 months, after starting treatment with atypical antipsychotics. Serum LIF-R concentrations were significantly increased 2 and 4 months after starting treatment with atypical antipsychotics. It is concluded that: (1) schizophrenia is characterized by an activation of both pro-inflammatory and anti-inflammatory aspects of cell-mediated immunity; (2) prolonged treatment with atypical antipsychotics may increase the anti-inflammatory capacity of the serum in schizophrenic patients by increasing serum LIF-R concentrations; and (3) short-term treatment with clozapine may induce signs of immune activation which disappear upon prolonged treatment.

Adult↗
PubMed2000

Partial impairment of cytokine responses in Tyk2-deficient mice.

To assess the role of the Janus kinase (Jak) family member Tyk2, we have generated Tyk2-/- mice. In contrast to other Jaks, where inactivation leads to a complete loss of the respective cytokine receptor signal, Tyk2-/- mice display reduced responses to IFNalpha/beta and IL-12 and a selective deficiency in Stat3 activation in these pathways. Unexpectedly, IFNgamma signaling is also impaired in Tyk2-/- mice. Tyk2-/- macrophages fail to produce nitric oxide upon lipopolysaccharide induction. Tyk2-/- mice are unable to clear vaccinia virus and show a reduced T cell response after LCMV challenge. These data imply a selective contribution of Tyk2 to the signals triggered by various biological stimuli and cytokine receptors.

Animals↗
PubMed1997

Isolation and characterization of a leukemia inhibitory factor-independent embryonic stem cell line.

Leukemia inhibitory factor (LIF) is a mammalian cytokine that has a wide range of physiological activities, including the inhibition of differentiation of embryonic stem (ES) cells. We have used insertional mutagenesis in an attempt to isolate molecules that participate in LIF signal transduction via the LIF receptor. Using a robust screen for undifferentiated cells, we have isolated one ES cell line, Poly 27, that does not require exogenous LIF to remain undifferentiated in vitro. We present evidence that Poly 27 is not irreversibly committed to an undifferentiated phenotype, but can differentiate in vitro if cultured in the presence of chemical differentiating agents, while in syngeneic mice Poly 27 cells form tumours which are composed largely of undifferentiated cells. We have characterized the mechanism of factor independence in Poly 27, and shown it to be a result of autocrine LIF production. This LIF production is potentially the result of a mutation in a gene critically involved in regulating LIF production in ES cells.

Animals↗
PubMed2002

Expression of leukemia inhibitory factor (LIF)/interleukin-6 family cytokines and receptors during in vitro osteogenesis: differential regulation by dexamethasone and LIF.

The leukemia inhibitory factor/interleukin-6 (LIF/IL-6) family of cytokines is known to play a major role in bone physiology. Although much work has focused on the regulation of bone resorption by IL-6 and related cytokines, their effects on osteoblast development and bone formation have not been as well studied. Previously, we reported that LIF inhibits, in a non-IL-6-dependent manner, osteoblast differentiation and bone nodule formation in the rat calvaria (RC) model, an effect that is antagonized by dexamethasone (Dex). The culture time-sensitive window suggested that LIF targets late preosteoblasts or early osteoblasts, and that this stage-specific effect coincided with a period of low endogenous production of LIF and IL-6. To detect potential crosstalk between members of this family, we have extended these observations by assessing the expression levels of other LIF/IL-6 cytokines (CNTF, OSM, IL-11, CT-1) and their receptors in the same RC cell model treated with or without LIF or Dex. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that IL-11 and its receptor, CNTF and its receptor, LIFR, and gp130 were constitutively expressed throughout the culture period. Expression of CT-1 and OSM increased with culture time - that is, with osteoblast differentiation - whereas the specific receptor for OSM (OSMR) was highly expressed at early timepoints and either plateaued or decreased thereafter. Continuous treatment with Dex (10(-8) mol/L) inhibited the endogenous production of IL-6, LIF, OSM, IL-11R, and OSMR, but had no detectable effect on the expression of IL-11, CT-1, CNTF, CNTFR, LIFR, or gp130. Finally, treatment with exogenously added LIF stimulated IL-6, LIF, LIFR, and OSMR, but had no other detectable effects. These data indicate that multiple members of the LIF/IL-6 family and their receptors are expressed in RC cell cultures, and are differentially regulated by Dex and LIF, suggesting that these cytokines play a complex and interdependent role, further modulated by glucocorticoid levels, in osteoprogenitor differentiation and bone nodule formation.

Animals↗
PubMed2001

Effects of pregnancy and delivery on the availability of plasma tryptophan to the brain: relationships to delivery-induced immune activation and early post-partum anxiety and depression.

BACKGROUND: There is now evidence that the availability of plasma tryptophan is decreased during pregnancy and the puerperium and also in patients with major depression and inflammation. The aims of the present study were to examine: (i) the effects of pregnancy and delivery on plasma tryptophan and the amino acids known to compete for the same cerebral uptake mechanism (CAAs), valine, leucine, tyrosine, phenylalanine and isoleucine; (ii) the relationships between the availability of plasma tryptophan and postpartum depression or anxiety; and (iii) the relationships between the availability of plasma tryptophan to the brain and inflammatory markers, such as serum interleukin-6 (IL-6), interleukin-1 receptor-antagonist (IL-1RA) and the leukaemia inhibitory factor receptor (LIF-R). METHODS: The above variables were measured in 13 healthy non-pregnant and in 98 pregnant women 3 to 6 days before delivery and 1 and 3 days after delivery. On each occasion the parturient women completed the state version of Spielberger State-Trait Anxiety Inventory (STAI) and the Zung Depression Rating Scale (ZDS). RESULTS: Plasma tryptophan and the tryptophan/CAA ratio were significantly lower at the end of term and after delivery than in the plasma of non-pregnant, healthy women. The tryptophan/CAA ratio was significantly lower in the early puerperium than at the end of term. There were no significant relationships between the availability of plasma tryptophan and either post-partum depression or changes in the STAI or ZDS scores in the early puerperium. The changes in the tryptophan/CAA ratio from the end of term to the early puerperium were significantly and inversely related to serum IL-6, IL-IRA and LIF-R. CONCLUSIONS: The results show that the reduction in the availability of plasma tryptophan from the end of term to the early puerperium is related to immune activation; and that the lowered availability of plasma tryptophan is not related either to depressive or anxiety symptoms in the early puerperium or to post-partum depression ensuing some months later.

Adult↗
PubMed2003

A family of leukemia inhibitory factor-binding peptides that can act as antagonists when conjugated to poly(ethylene glycol).

A panel of six naïve 14-residue random peptide libraries displayed polyvalently on M13 phage was pooled and sorted against human leukemia inhibitory factor (LIF). After four rounds of selection, a single large family of peptides with the consensus sequence XCXXXXG(A/S)(D/E)(W/F)WXCF was found to bind specifically to LIF. Peptides within this family did not bind related members of the interleukin-6 family of cytokines, nor to murine LIF that has 80% sequence identity with human LIF. A representative peptide from this family was synthesized and found to bind to LIF with an affinity of approximately 300 nM. The phage-displayed form of this peptide was able to compete with the LIF receptor alpha chain (LIFR) for binding to LIF; however, the free synthetic peptide was unable to inhibit LIF-LIFR binding or inhibit LIF bioactivity in vitro. Using a panel of human/murine chimeric LIF molecules, the peptide-binding site on LIF was mapped to a groove located between the B and the C helices of the LIF structure, which is distinct from the surfaces involved in binding to receptor. To mimic the effect of the phage particle and convert the free peptide into an antagonist of LIFR binding, a 40 kDa poly(ethylene glycol) (PEG) moiety was conjugated to the synthetic LIF-binding peptide. This PEG-peptide conjugate was found to be both an antagonist of LIF-LIFR binding and of LIF signaling in engineered Ba/F3 cells expressing LIFR and the gp130 coreceptor.

Amino Acid Sequence↗
PubMed1998

Growth inhibition of newly established human glioma cell lines by leukemia inhibitory factor.

We have established three new cell lines deriving from malignant human gliomas. The cell lines were described in terms of both morphology and growth characteristics. Most cells in all three cell lines expressed the neuroepithelial marker protein GFAP. In terms of growth characteristics, the cells showed only slight differences. The cell lines showed no expression of the neural form of the c-src gene, pp60c-srcN, but did express the ubiquitous form, pp60c-src. The established glioma cell lines were also examined for expression of members of the neuropoietic cytokine family, CNTF and LIF, and their respective receptor components CNTFRalpha, LIFRbeta and gp130. With the exception of CNTFRalpha both the ligands and their receptor components were expressed in similar amounts in all three cell lines. The presence of ligand and receptor prompted us to study the effects of exogenously supplied factors on the growth of the glioma cell lines. Whereas LIF induced a high c-fos expression, only low c-fos induction was observed upon CNTF treatment. Accordingly, CNTF did not have any noticeable effects on glioma cell growth in culture, while LIF mediated an inhibiting effect on the growth of the three glioma cell lines in culture.

Aneuploidy↗
PubMed1998

Expression of leukemia inhibitory factor and its receptor in breast cancer: a potential autocrine and paracrine growth regulatory mechanism.

Leukemia inhibitory factor (LIF) is a pluripotent cytokine which has a diverse array of effects on hematopoietic and epithelial cells. Depending on the nature of the target cells, these effects can be growth-stimulatory or growth-inhibitory. Receptors for leukemia inhibitory factor (LIFR) have been identified on a variety of hematopoietic and epithelial cells. We have recently demonstrated in vitro growth stimulation of human breast cancer cells, both primary tumors and cultured cell lines, by LIF. To begin to understand the in vivo relevance of these observations, we investigated the expression of LIF and LIFR in human breast cancer specimens. Specimens from 50 cases were immunostained with mouse monoclonal antibodies D62.3 and M1 (to stain for LIF and LIFR, respectively). LIF expression was observed in 78% of the specimens and correlated with favorable biological features, i.e. low S-phase fraction (SPF) (P = 0.001) and diploidy (P = 0.08). LIFR expression was observed in 80% of the tumors and correlated with the presence of estrogen receptor (ER) (P = 0.04) and diploidy (P = 0.07). Coexpression of LIF and LIFR was associated with diploidy (P = 0.02) and low SPF (P = 0.05). LIF staining was primarily cytoplasmic whereas LIFR staining was cytoplasmic in the majority of cases and membranous in a minority of cases. The presence of LIFR in the primary tumor specimens correlated with the growth stimulation of tumor cells (derived from the same specimens) by exogenous LIF in methylcellulose colony assays. The findings support a widespread but probably complex role for LIF and LIFR in breast tumor growth regulation which should be investigated in greater detail in larger cohorts of tumors.

Breast Neoplasms↗
PubMed1997

Refolding of soluble leukemia inhibitory factor receptor fusion protein (gp 190 sol DAF) from urea.

The insoluble inclusion bodies of soluble leukemia inhibitory factor receptor fusion protein (gp 190 sol DAF) was solubilized in 8 M urea on the unfolding transitions, and several factors on the aggregate formation were indirectly analyzed for the refolding of gp 190 sol DAF. Results indicate that the refolding yield can be considerably increased at lowering concentration of the unfolding protein, a little soluble protein with the slow refolding appears in the process of the aggregate formation and the concentration of the denaturant must be down to a minimum level for its refolding.

Glycerol↗