We identified a CpG island at the 5' end of murine leukemia inhibitory factor gene (LIF). The CpG island is 0.6 kb long and covers most of the first exon and first intron. The region is non-methylated, its G+C content is 65% and relative frequency of CpG dinucleotide is 0.7. The block of 150 nucleotides, which is 72% conserved between murine, human, ovine and porcine genes, is a part of the CpG island. Two DNA fragments from this CpG island interact with nuclear proteins from NIH 3T3 cells. One fragment partially covers the block of conserved nucleotides. Human, ovine and porcine LIF genes also contain G+C- and CpG-rich sequences in the corresponding region.

• MeSH
• cytosin MeSH
• exony MeSH
• guanin MeSH
• inhibitory růstu genetika   MeSH
• interleukin-6 * MeSH
• introny MeSH
• konzervovaná sekvence MeSH
• leukemický inhibiční faktor MeSH
• lidé MeSH
• lymfokiny genetika   MeSH
• metylace MeSH
• myši MeSH
• ovce MeSH
• sekvence nukleotidů MeSH
• Southernův blotting MeSH
• zastoupení bazí MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytosin MeSH
• guanin MeSH
• inhibitory růstu MeSH
• interleukin-6 * MeSH
• leukemický inhibiční faktor MeSH
• LIF protein, human MeSH Prohlížeč
• Lif protein, mouse MeSH Prohlížeč
• lymfokiny MeSH

Leukemia inhibitory factor (LIF) is a cytokine that exhibits proliferation, survival and differentiation in a wide range of cell types. Here we show that LIF potentiates retinoic acid-mediated neural induction in pluripotent P19 embryonal carcinoma cells. This activity of LIF was demonstrated by a profounded neural morphology followed by increased expression of neural-specific proteins (N-CAM, III beta-tubulin, and GAP-43), up-regulation of early neural lineage-specific gene Mash-1, and down-regulation of early endoderm-specific genes -fetoprotein and GATA-4. Moreover, LIF also slows growth and increases the level of apoptosis in differentiating cells.

• MeSH
• buněčná diferenciace účinky léků   fyziologie   MeSH
• embryo savčí MeSH
• interleukin-6 farmakologie   MeSH
• leukemický inhibiční faktor MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• neurony cytologie   účinky léků   MeSH
• synergismus léků MeSH
• tretinoin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• interleukin-6 MeSH
• leukemický inhibiční faktor MeSH
• Lif protein, mouse MeSH Prohlížeč
• tretinoin MeSH

OBJECTIVES: IgA nephropathy (IgAN) is thought to involve an autoimmune process wherein galactose-deficient IgA1 (Gd-IgA1), recognized as autoantigen by autoantibodies, forms pathogenic immune complexes. Mounting evidence has implicated abnormal activation of some protein-tyrosine kinases (PTKs) in IgAN. Furthermore, genome-wide association studies (GWAS) of IgAN provided insight into disease pathobiology and genetics. A GWAS locus on chromosome 22q12 contains genes encoding leukemia inhibitory factor (LIF) and oncostatin M, interleukin (IL)-6-related cytokines implicated in mucosal immunity and inflammation. We have previously shown that IL-6 mediates overproduction of Gd-IgA1 through aberrant STAT3 activation. Here, we show that LIF enhanced production of Gd-IgA1 in IgA1-secreting cells of patients with IgAN and provide initial analyses of LIF signaling. METHODS: We characterized LIF signaling that is involved in the overproduction of Gd-IgA1, using IgA1-secreting cell lines derived from peripheral blood of patients with IgAN and healthy controls (HC). We used global PTK activity profiling, immunoblotting, lectin ELISA, and siRNA knock-down. RESULTS: LIF stimulation did not significantly affect production of total IgA1 in IgA1-secreting cells from patients with IgAN or HC. However, LIF increased production of Gd-IgA1, but only in the cells from patients with IgAN. LIF stimulation enhanced phosphorylation of STAT1 in IgA1-secreting cells from patients with IgAN to a higher degree than in the cells from HC. siRNA knock-down of STAT1 blocked LIF-mediated overproduction of Gd-IgA1. Unexpectedly, this abnormal phosphorylation of STAT1 in IgA1-secreting cells from patients with IgAN was not mediated by JAK, but rather involved activation of Src-family PTKs (SFKs). CONCLUSION: Abnormal LIF/STAT1 signaling represents another pathway potentially leading to overproduction of Gd-IgA1 in IgAN, providing possible explanation for the phenotype associated with chromosome 22q12 GWAS locus. Abnormal LIF/STAT1 signaling and the associated SFKs may represent potential diagnostic and/or therapeutic targets in IgAN.

• Klíčová slova
• Aberrant O-glycosylation, Autoantigen, IgA nephropathy, Leukemia inhibitory factor, O-glycans,
• Publikační typ
• časopisecké články MeSH

To characterize the impact of the potentially functional mutation--the G to A transition at the position 3400 of the leukemia inhibitory factor (LIF; a pluripotent cytokine that plays a central role in the control of the embryo implantation) gene that leads to the exchange of valine with methionine at codon 64 we evaluated the association of the LIF gene mutation and the levels of antiphospolipid antibodies (aPLs) in the peripheral blood of infertile women (the aPLs examination was part of our routine immunological test during the infertility check-up). Eight infertile mutation-positive women were diagnosed with idiopathic infertility (n=5) and endometriosis (n=3) and their levels of aPLs in serum were compared with 115 infertile women without any LIF gene mutation. Enzyme-linked immunosorbent assay was used for the detection of seven antiphospholipid antibodies; the results were statistically assessed by the Fisher's 2 by 2 exact test to evaluate the association of the LIF gene mutations and aPLs in serum of infertile patients. The presence of aPLs was significantly higher in our study group (100%) than in 30% of aPLs-positives in control infertile patients (p = 0.0035) which indicates that the aPLs are elevated in women with LIF gene mutations.

• MeSH
• antifosfolipidové protilátky krev   imunologie   MeSH
• bodová mutace * MeSH
• dospělí MeSH
• ELISA MeSH
• endometrióza krev   genetika   imunologie   MeSH
• heteroduplexní analýza metody   MeSH
• leukemický inhibiční faktor genetika   MeSH
• lidé MeSH
• sekvenční analýza DNA MeSH
• ženská infertilita krev   genetika   imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• antifosfolipidové protilátky MeSH
• leukemický inhibiční faktor MeSH
• LIF protein, human MeSH Prohlížeč

OBJECTIVE: Leukemia inhibitory factor (LIF) is one of the key cytokines in the embryo implantation regulation. We investigated the prevalence of the LIF gene mutations in the population of infertile women that consisted of nulligravid and secondary infertile patients. STUDY DESIGN: We designed a LIF gene mutation screening method that is based on the Temperature Gradient Gel Electrophoresis (TGGE). The population to screen consisted of 176 infertile women including group A of 147 nulligravid women and group B of 29 women with secondary infertility that had a history of either miscarriage or an ectopic pregnancy but no live births. The control population was comprised of 75 healthy fertile subjects. The groups of fertile controls and infertile patients were compared for statistically significant differences using the t-test. RESULTS: Six potentially functional LIF gene mutations, the G to A transitions at the position 3400 leading to the valin to methionin exchange at codon 64 (V64M) in the AB loop region of the LIF protein, were detected. All of the six positive women were infertile. Four of them were nulligravid and two of them had history of spontaneous conception followed by early miscarriage. No positive TGGE samples were identified in the control group, which means that the frequency of functionally relevant mutations of the LIF gene in infertile women is significantly enhanced in comparison with controls (P<0.05, t-test). CONCLUSION: The results suggest that the LIF gene mutations affect fertility. Even though they occur infrequently, their impact on molecular events during early phases of pregnancy should be further established.

• MeSH
• bodová mutace * MeSH
• dospělí MeSH
• elektroforéza v agarovém gelu metody   MeSH
• genetické testování metody   MeSH
• gravidita MeSH
• kodon MeSH
• leukemický inhibiční faktor genetika   MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• polymerázová řetězová reakce metody   MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• těhotenství MeSH
• ženská infertilita genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kodon MeSH
• leukemický inhibiční faktor MeSH
• LIF protein, human MeSH Prohlížeč

Locally secreted cytokines of both the embryonic and the endometrial origin control the implantation process. The defects in their signaling that lead to unfavorable environment within the uterus may cause embryo implantation failure. The leukemia inhibitory factor (LIF), interleukin-11 (IL-11) as well as IL-12/IL-15/IL-18 system are regarded to be important signaling vectors. LIF plays an essential role in the preimplantation embryo development and the blastocyst implantation and its gene mutations in women contribute to the implantation failure and subsequent infertility. IL-11 signaling has been shown to be required for the uterine decidualization response as well as for the hatching and attachment of blastocysts. The IL-12/IL-15/IL-18 system interacts with endometrial leukocytes, particularly with NK cells, and influences directly the local angiogenesis and tissue remodeling. Differences in the levels of endometrial leukocytic subpopulations and in the patterns of intra-uterine cytokine concentrations that are observed between fertile and infertile women contribute to infertility probably by affecting the embryonic maternal dialogue during the implantation and early placentation period. Focusing on this cross talk promises to open new era in assisted reproduction techniques that will be based on diagnostics of missing signaling molecules and impairments of uterine receptivity as well as on therapeutic applications of individualized embryo culture and transfer media.

• MeSH
• buňky NK imunologie   MeSH
• cytokiny fyziologie   MeSH
• embryo savčí imunologie   MeSH
• endometrium imunologie   MeSH
• homeostáza MeSH
• implantace embrya genetika   imunologie   MeSH
• interleukin-6 genetika   fyziologie   MeSH
• leukemický inhibiční faktor MeSH
• lidé MeSH
• mutace * MeSH
• signální transdukce MeSH
• těhotenství MeSH
• ženská infertilita genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cytokiny MeSH
• interleukin-6 MeSH
• leukemický inhibiční faktor MeSH
• LIF protein, human MeSH Prohlížeč

The leukaemia inhibitory factor is a cytokine that exhibits pleiotropic activities in a wide range of cell types. There are evidences that leukaemia inhibitory factor-regulated signalling pathways are involved in cardiomyogesis and maintenance of cardiomyocytes. In the present work we studied the effect of leukaemia inhibitory factor on cardiomyogenesis of embryonic stem cells together with the role of serum-born factors. We showed that leukaemia inhibitory factor had an inhibitory effect during both the induction and progression phases of cardiomyogenesis of embryonic stem cells. The leukaemia inhibitory factor-mediated inhibition of cardiomyogenesis was abolished by inhibitors of STAT3 activity. These results suggest that leukaemia inhibitory factor- activated STAT3 is responsible for the inhibition of cardiomyogenesis in embryonic stem cells.

• MeSH
• buněčná diferenciace * účinky léků   fyziologie   MeSH
• embryo savčí MeSH
• embryonální indukce účinky léků   MeSH
• embryonální kmenové buňky cytologie   účinky léků   metabolismus   fyziologie   MeSH
• kardiomyocyty cytologie   účinky léků   metabolismus   fyziologie   MeSH
• leukemický inhibiční faktor metabolismus   fyziologie   MeSH
• myši MeSH
• signální transdukce účinky léků   fyziologie   MeSH
• srdce embryologie   MeSH
• transkripční faktor STAT3 metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• leukemický inhibiční faktor MeSH
• Lif protein, mouse MeSH Prohlížeč
• Stat3 protein, mouse MeSH Prohlížeč
• transkripční faktor STAT3 MeSH

Leukaemia inhibitory factor (LIF) has a wide variety of biological activities. While recent studies have focused on the role of LIF in osteoblast differentiation, the exact role of LIFR during the early stage of osteogenic differentiation remains unclear. We observed that LIFR expression gradually decreased during the early stage of osteogenic differentiation of hMSCs. To evaluate how LIFR regulates osteogenic differentiation in greater depth, we transfected hMSCs with LIFR overexpression and siRNA lentiviral plasmids. Cells were divided into four groups: a negative overexpression control group, a LIFR overexpression group, a negative siRNA control group, and a LIFR siRNA group. On different days (0, 3, and 6) of the osteogenic differentiation of hMSCs, alkaline phosphatase (ALP) activity was assayed with an ALP staining and activity assay kit. Cells were harvested to assess the mRNA and protein expression of LIF, LIFR, and osteogenesis-related factors (ALP; RUNX2; osteonectin) by qRT-PCR and western blot analyses, respectively. In addition, culture supernatants were tested for the LIF content by ELISA. Our results showed that overexpression of LIFR significantly suppressed the osteoblast differentiation of hMSCs. In contrast, LIFR siRNA markedly improved this osteoblast differentiation as determined by ALP staining and activity measurements. Moreover, RUNX2, ALP, and ONN expression was also significantly changed by altering LIFR expression. We further analysed the expression of LIF and LIFR, revealing consistent LIF and LIFR trends during the osteogenic differentiation of hMSCs. Together, these results suggested that LIFR may be a novel negative regulator during the early stage of hMSC osteogenic differentiation.

• MeSH
• alkalická fosfatasa metabolismus   MeSH
• barvení a značení MeSH
• buněčná diferenciace * MeSH
• buňky kostní dřeně cytologie   MeSH
• Lentivirus metabolismus   MeSH
• leukemický inhibiční faktor metabolismus   MeSH
• lidé MeSH
• mezenchymální kmenové buňky cytologie   metabolismus   MeSH
• osteogeneze * MeSH
• receptory OSM-LIF metabolismus   MeSH
• transdukce genetická MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkalická fosfatasa MeSH
• leukemický inhibiční faktor MeSH
• LIF protein, human MeSH Prohlížeč
• receptory OSM-LIF MeSH

OBJECTIVE: The leukemia inhibitory factor (LIF) is one of the most important signaling factors in the embryo-maternal cross talk during the embryo implantation. We investigated the prevalence of the LIF gene mutations in the population of infertile women and their impact on infertility treatment. DESIGN: A cohort study. SETTING: Department of Obstetrics and Gynecology, Faculty of Medicine and University Hospital of Charles University, Pilsen. SUBJECTS AND METHODS: The population to screen consisted of 399 infertile women. The control population was comprised of 202 healthy fertile subjects. For the mutational analysis, the temperature gradient gel electrophoresis (TGGE) followed by subsequent sequencing of the positive samples, had been used. The groups of fertile controls and infertile patients were compared for statistically significant difference using the Fisher's 2 by 2 Exact test. RESULTS: Twelve potentially functional LIF gene mutations, the G to A transversion at the position 3400 leading to the valin to methionin exchange at codon 64 (V64M) were detected in the group of infertile women. No mutations were identified in the control group, which means that the frequency of functionally relevant mutations of the LIF gene in infertile women is significantly enhanced in comparison with controls (P = 0.01, Fisher's 2 by 2 Exact test ). Seven of these patients were successfully treated by in vitro fertilization (IVF). CONCLUSION: The results suggest that the LIF gene mutation, the heterozygote G to A transition on the position 3400, affects fertility but the infertility treatment can succeed. Even though LIF gene mutations occur infrequently and can be overcome by infertility treatment, their impact on molecular events during early phases of pregnancy should be further elucidated.

• MeSH
• bodová mutace * MeSH
• fertilizace in vitro * MeSH
• heterozygot * MeSH
• leukemický inhibiční faktor genetika   MeSH
• lidé MeSH
• těhotenství MeSH
• ženská infertilita genetika   terapie   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• leukemický inhibiční faktor MeSH
• LIF protein, human MeSH Prohlížeč

Acute lymphoblastic leukemia (ALL) cells depend on the microenvironment of the host in vivo and do not survive in in vitro culture. Conversely, the suppression of non-malignant tissues is one of the leading characteristics of the course of ALL. Both the non-malignant suppression and malignant cell survival may be partly affected by soluble factors within the bone marrow (BM) environment. Here, we aimed to identify proteins in BM plasma of children with ALL that may contribute to ALL aggressiveness and/or the microenvironment-mediated survival of ALL cells. LBMp (leukemic bone marrow plasma) at the time of ALL diagnosis was compared to control plasma of bone marrow (CBMp) or peripheral blood (CPBp) using a cytokine antibody array. The cytokine antibody array enabled simultaneous detection of 79 proteins per sample. Candidate proteins exhibiting significantly different profiles were further analyzed and confirmed by ELISA. mRNA expression of one of the candidate proteins (TIMP1) was studied using quantitative reverse transcriptase polymerase chain reaction (qRTPCR). The cytokine antibody array experiments identified 23 proteins that differed significantly (p<0.05); of these, two proteins (TIMP1 and LIF) withstood the Bonferroni correction. In contrast, little difference was observed between CBMp and CPBp. At the diagnosis of ALL, changes in the soluble microenvironment are detectable in BM plasma. These changes probably participate in the pathogenesis and/or result from the changes in the cell composition.

• Klíčová slova
• bone marrow plasma, cytokine antibody array, pediatric acute lymphoblastic leukemia,
• MeSH
• akutní lymfatická leukemie krev   patologie   MeSH
• čipová analýza proteinů MeSH
• cytokiny krev   MeSH
• dítě MeSH
• kostní dřeň metabolismus   MeSH
• leukemický inhibiční faktor biosyntéza   MeSH
• lidé MeSH
• messenger RNA biosyntéza   MeSH
• nádorové biomarkery krev   MeSH
• tkáňový inhibitor metaloproteinasy 1 biosyntéza   krev   MeSH
• viabilita buněk MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• leukemický inhibiční faktor MeSH
• LIF protein, human MeSH Prohlížeč
• messenger RNA MeSH
• nádorové biomarkery MeSH
• TIMP1 protein, human MeSH Prohlížeč
• tkáňový inhibitor metaloproteinasy 1 MeSH