Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The suppressor of cytokine-signaling (SOCS) proteins act as negative-feedback inhibitors of cytokine and growth-factor-induced signal transduction. In vivo studies have implicated SOCS3 as a negative regulator of signaling downstream of gp130, the receptor subunit shared by IL-6-like cytokines. Mice lacking SOCS3 die at midgestation because of placental failure, and SOCS3 ablation in a cell-type-specific manner results in changes in the functional outcome of gp130 signaling in response to IL-6. In this study, we show that genetic reduction of leukemia-inhibitory factor (LIF) production by embryo-derived tissues is sufficient to prevent the placental defect. This establishes LIF signaling as a major physiological regulator of trophoblast differentiation in vivo. Mice deficient in both SOCS3 and LIF are born in predicted numbers and appear normal at birth but exhibit failure to thrive and high neonatal mortality. Adult SOCS3-null mice on a LIF-null background succumb to a spontaneous fatal inflammatory disease characterized by neutrophilia and inflammatory-cell tissue infiltrates. The disease spectrum mimics that seen in mice with a conditional deletion of SOCS3 in hematopoietic and endothelial cells, extending the evidence for a major role for SOCS3 in the homeostatic regulation of the inflammatory response and indicates that LIF is not required for this process.
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PMID:Genetic reduction of embryonic leukemia-inhibitory factor production rescues placentation in SOCS3-null embryos but does not prevent inflammatory disease. 1625 63

Human T-cell leukemia virus type-I (HTLV-I) encodes for the viral protein Tax, which is known to significantly disrupt transcriptional control of cytokines, cytokine receptors and other immuno-modulatory proteins in T cells. Specific dysregulation of these factors can alter the course and pathogenesis of infection. Soluble interleukin-6 receptor (sIL-6R) was shown to circulate at elevated levels in HTLV-I-infected patients, and high expressions of IL-6R and sIL-6R by HTLV-I-infected T cells were clinically and experimentally associated with Tax activity. To examine roles of Tax in expression of the IL-6R gene, the JPX-9 cell line was used, which is derived from Jurkat cell line expressing Tax cDNA. Over-expression of Tax enhanced IL-6R expression but not in Tax mutant JPX-9/M cell line. The clinical relevance of these observations was further demonstrated by ELISA using sera obtained from HTLV-I-infected patients. Our results revealed that sIL-6R levels were apparently elevated in HAM/TSP patients who were expressing Tax in their cells, while ATL patients' cells barely expressed Tax. HTLV-I-infected T-cell lines stimulated by IL-6/sIL-6R showed gp130-mediated STAT3 activity. IL-6/sIL-6R enhanced proliferation of HTLV-I-infected T cells in association with activation of STAT3. Consequently, Tax-mediated regulations of IL-6R and sIL-6R observed in HTLV-I-associated disorders may contribute to proliferation of HTLV-I-infected T cells through activation of inducible STAT3, and ultimately affect malignant growth and transformation of T cells by HTLV-I.
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PMID:Human T-cell leukemia virus type-I Tax induces expression of interleukin-6 receptor (IL-6R): Shedding of soluble IL-6R and activation of STAT3 signaling. 1655 88

Leukemia inhibitor factor (LIF) has been shown to potently inhibit HIV-1 replication in vitro and in human organ explant cultures. Furthermore, LIF activates the Jak/Stat signaling pathway with which many viruses, including HIV-1, interfere. We used CXCR4 and the LIF signaling receptor (gp130)-expressing cMAGI cells transfected with CD4, CCR5, and HIV-LTR-beta-galactosidase as a model system to investigate the potential involvement of Stat proteins in the anti-HIV-1 effect of LIF. Pretreatment with recombinant human (rh)LIF resulted in a significantly reduced uptake of HIV-1(BaL) , HIV-1(LAI), and SIVmac251 viral particles without affecting uptake of murine leukemia retroviral particles. HIV-1(BaL), HIV-1(LAI), as well as rhLIF selectively induced phosphorylation of Stat 3 but not Stat 1 or Stat 5. However, treatment of cMAGI cells with rhLIF prior to HIV-1 infection downregulated the HIV-1-mediated Stat 3 phosphorylation. In addition, peripheral blood mononuclear cells (PBMCs) transfected with Stat 3 siRNA prior to HIV-1(LAI) or HIV-1(BaL) infection produced significantly less HIV-1 p24 antigen as compared to nontransfected HIV-1(LAI) and HIV-1(BaL)-infected PBMCs. Thus, the Jak/Stat signaling pathway is important for the HIV-1 replication life cycle and rhLIF excerts its anti-HIV-1 activity by disrupting this signaling cascade.
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PMID:Leukemia inhibitor factor (LIF) inhibits HIV-1 replication via restriction of stat 3 activation. 1741 73

Leukaemia inhibitory factor (LIF) is a cytokine, which is associated with reproductive processes such as embryo development and implantation. The objectives of this study were to detect the presence of LIF receptor (LIFR) and glycoprotein 130 (gp 130) in the human Fallopian tube, endometrium and preimplantation embryo and to study the effect of mifepristone on the expression of LIFR and gp130 in the Fallopian tube. Twenty-two healthy fertile women received a single dose of 200 mg mifepristone or placebo immediately after ovulation (LH + 2). Biopsies were obtained from the Fallopian tubes during laparoscopic sterilization once between days LH + 4 and LH + 6 and from endometrium once between days LH + 6 and LH + 8. Preimplantation embryos were received from couples undergoing in vitro fertilization treatment. Immunohistochemistry was used to detect the presence of LIFR and gp130 in the Fallopian tube, endometrium and preimplantation embryo. Real-time PCR was used to study LIFR and gp130 expression in the Fallopian tube and endometrium. LIFR and gp130 were localized in the Fallopian tube, preimplantation embryo and endometrium. LIFR was more abundant in the Fallopian tube than in the endometrium. In the blastocyst, the staining of gp130 was mainly localized in the inner cell mass, whereas LIFR was expressed in all cells. The presence of LIFR and gp130 in the Fallopian tube and preimplantation embryo indicates a role for LIF in communication between the embryo and the Fallopian tube. Mifepristone did not affect the expression of LIFR and gp130 in the Fallopian tube, nor in the endometrium suggesting that progesterone might not be directly involved in the regulation of LIFR or gp130.
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PMID:Leukaemia inhibitory factor receptor and gp130 in the human Fallopian tube and endometrium before and after mifepristone treatment and in the human preimplantation embryo. 1743 Sep 84

Implantation, a critical step for establishing pregnancy, requires molecular and cellular events resulting in healthy uterine growth and differentiation, blastocyst adhesion, invasion and placental formation. Successful implantation requires a receptive endometrium, a normal and functional embryo at the blastocyst stage and a synchronized dialogue between maternal and embryonic tissues. In addition to the main role of sex steroids, the complexity of embryo implantation and placentation is exemplified by the number of cytokines and growth factors with demonstrated roles in these processes. Disturbances of the normal expression and action of these cytokines result in absolute or partial failure of implantation and abnormal placental formation in mice and humans. Members of the gp130 cytokine family, interleukin (IL)-11 and leukaemia inhibitory factor, the transforming growth factor-beta superfamily, colony-stimulating factors, and the IL-1 and IL-15 systems are all crucial for successful implantation. In addition, chemokines are important both in recruiting specific cohorts of leukocytes to the implantation site, and in trophoblast trafficking and differentiation. This review provides discussion on embryonic and uterine factors that are involved in the process of implantation in autocrine, paracrine and/or juxtacrine manners at hormonal, cellular, and molecular levels.
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PMID:Basic aspects of implantation. 1806 73

gp130-Related cytokines such as interleukin-6 and leukemia-inhibitory factor (LIF) act on the adenohypophysis in a paracrine manner, affecting both its differentiation and the function of specific cell types, notably the proopiomelanocortin (POMC) cells. They act on POMC cells in synergism with corticotrophin-releasing hormone, inducing ACTH secretion. gp130-Related cytokines as well as their receptors are expressed in the pituitary. LIF knockout mice show reduced stress-induced ACTH secretion, which can be restored by LIF replacement, suggesting a physiologic role for LIF.
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PMID:gp130-Related Cytokines and Their Receptors in the Pituitary. 1840 60

gp130-Related cytokines such as interleukin-6 and leukemia-inhibitory factor (LIF) act on the adenohypophysis in a paracrine manner, affecting both its differentiation and the function of specific cell types, notably the proopiomelanocortin (POMC) cells. They act on POMC cells in synergism with corticotrophin-releasing hormone, inducing ACTH secretion. gp130-Related cytokines as well as their receptors are expressed in the pituitary. LIF knockout mice show reduced stress-induced ACTH secretion, which can be restored by LIF replacement, suggesting a physiologic role for LIF.
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PMID:gp130-Related cytokines and their receptors in the pituitary. 1840 28

gp130 is a shared receptor for at least nine cytokines and can signal either as a homodimer or as a heterodimer with Leukemia Inhibitory Factor Receptor (LIF-R). Here, we biophysically and structurally characterize the full-length, transmembrane form of a quaternary cytokine receptor complex consisting of gp130, LIF-R, the cytokine Ciliary Neurotrophic Factor (CNTF), and its alpha receptor (CNTF-Ralpha). Thermodynamic analysis indicates that, unlike the cooperative assembly of the symmetric gp130/Interleukin-6/IL-6Ralpha hexameric complex, CNTF/CNTF-Ralpha heterodimerizes gp130 and LIF-R via noncooperative energetics to form an asymmetric 1:1:1:1 complex. Single particle electron microscopic analysis of the full-length gp130/LIF-R/CNTF-Ralpha/CNTF quaternary complex elucidates an asymmetric structural arrangement, in which the receptor extracellular and transmembrane segments join as a continuous, rigid unit, poised to sensitively transduce ligand engagement to the membrane-proximal intracellular signaling regions. These studies also enumerate the organizing principles for assembly of the "tall" class of gp130 family cytokine receptor complexes including LIF, IL-27, IL-12, and others.
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PMID:Structural organization of a full-length gp130/LIF-R cytokine receptor transmembrane complex. 1877 32

Leukaemia inhibitory factor (LIF) is a member of the IL-6 cytokine family which signals through cognate receptors and activates target genes involved in survival, apoptosis, proliferation, differentiation and suppression of differentiation in different cell types. Binding of LIF to the LIFRalpha/gp130 receptor complex has been shown to activate the Janus kinase-signal transducer and activator of transcription 3 pathway. Here we show that activation of naturally occurring and adaptive regulatory T cells leads to increased LIF expression which is abrogated by cyclic adenosine monophosphate. Furthermore, the LIF receptors gp130 and LIFRalpha are upregulated on the surface of activated T cells and signal transducer and activator of transcription 3 phosphorylation is increased. Interestingly, LIF was not required for suppressive function but rather appeared to have a stimulatory effect on T cells that served to modulate and counteract immunosuppression by regulatory T cells.
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PMID:Human naturally occurring and adaptive regulatory T cells secrete high levels of leukaemia inhibitory factor upon activation. 1878 68

The mechanism by which Suppressor of Cytokine Signaling-3 (SOCS3) negatively regulates cytokine signaling has been widely investigated using over-expression studies in cell lines and is thought to involve interactions with both the gp130 receptor and JAK1. Here, we compare the endogenous JAK/STAT signaling pathway downstream of Leukemia Inhibitory Factor (LIF) signaling in wild type (WT) Embryonic Stem (ES) cells and in ES cells lacking either the entire Socs3 gene or bearing a truncated form of SOCS3 (SOCS3DeltaSB) lacking the C-terminal SOCS box motif (SOCS3(DeltaSB/DeltaSB)). In SOCS3(DeltaSB/DeltaSB) cells phosphorylated JAK1 accumulated at much higher levels than in WT cells or even cells lacking SOCS3 (SOCS3(-/-)). In contrast enhanced activation of STAT3 and SHP2 was seen in SOCS3(-/-) cells. Size exclusion chromatography of cell extracts showed that in unstimulated cells, JAK1 was exclusively associated with receptors but following cytokine stimulation hyperphosphorylated JAK1 (pJAK1) appeared to dissociate from the receptor complex in a manner independent of SOCS3. In WT and SOCS3(DeltaSB/DeltaSB) cells SOCS3 was associated with pJAK1. The data suggest that dissociation of activated JAK1 from the receptor results in separate targeting of JAK1 for proteasomal degradation through a mechanism dependent on the SOCS3 SOCS box thus preventing further activation of STAT3.
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PMID:Deletion of the SOCS box of suppressor of cytokine signaling 3 (SOCS3) in embryonic stem cells reveals SOCS box-dependent regulation of JAK but not STAT phosphorylation. 1905 87


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