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Molecular Therapy : the Journal of the... Feb 2023Leukemia inhibitory factor (LIF) is a pleiotropic cytokine of the interleukin-6 (IL-6) superfamily. LIF was initially discovered as a factor to induce the... (Review)
Review
Leukemia inhibitory factor (LIF) is a pleiotropic cytokine of the interleukin-6 (IL-6) superfamily. LIF was initially discovered as a factor to induce the differentiation of myeloid leukemia cells and thus inhibit their proliferation. Subsequent studies have highlighted the multi-functions of LIF under a wide variety of physiological and pathological conditions in a highly cell-, tissue-, and context-dependent manner. Emerging evidence has demonstrated that LIF plays an essential role in the stem cell niche, where it maintains the homeostasis and regeneration of multiple somatic tissues, including intestine, neuron, and muscle. Further, LIF exerts a crucial regulatory role in immunity and functions as a protective factor against many immunopathological diseases, such as infection, inflammatory bowel disease (IBD), and graft-verse-host disease (GVHD). It is worth noting that while LIF displays a tumor-suppressive function in leukemia, recent studies have highlighted the oncogenic role of LIF in many types of solid tumors, further demonstrating the complexities and context-dependent effects of LIF. In this review, we summarize the recent insights into the roles and mechanisms of LIF in stem cell homeostasis and regeneration, immunity, and cancer, and discuss the potential therapeutic options for human diseases by modulating LIF levels and functions.
Topics: Humans; Leukemia Inhibitory Factor; Growth Inhibitors; Cell Differentiation; Interleukin-6; Leukemia Inhibitory Factor Receptor alpha Subunit; Lymphokines
PubMed: 36575793
DOI: 10.1016/j.ymthe.2022.12.016 -
International Journal of Cell Cloning Mar 1991Leukemia inhibitory factor (LIF) is a glycoprotein able to enforce differentiation and/or suppress clonogenic self-renewal in a number of myeloid leukemic cell lines.... (Review)
Review
Leukemia inhibitory factor (LIF) is a glycoprotein able to enforce differentiation and/or suppress clonogenic self-renewal in a number of myeloid leukemic cell lines. When acting on normal embryonic stem cells, it has the opposite action of preventing differentiation commitment. LIF is not a proliferative factor when acting alone on normal hemopoietic cells, but can potentiate the action of interleukin 3 on blast cell and megakaryocyte precursors. When injected in vivo, LIF stimulates rises in megakaryocyte numbers and platelet levels. LIF also exhibits striking functional effects on a wide range of other cells including hepatic parenchymal cells, neurones, adipocytes, osteoblasts and gonadal cells. The polyfunctionality of LIF suggests strongly that it is normally intended to be produced locally and act as a local regulator. Despite its wide range of actions, LIF remains a promising candidate for clinical use in thrombocytopenia and myeloid leukemia.
Topics: Animals; Calcium; Cell Differentiation; Cell Line, Transformed; Growth Inhibitors; Humans; Interleukin-6; Leukemia Inhibitory Factor; Lymphokines; Receptors, Cell Surface; Serum Albumin; Stem Cells
PubMed: 1645391
DOI: 10.1002/stem.5530090201 -
Cell Structure and Function Feb 2001Angiogenesis is an essential biological process not only in embryogenesis but also in the progression of a variety of major diseases such as cancer, diabetes and... (Review)
Review
Angiogenesis is an essential biological process not only in embryogenesis but also in the progression of a variety of major diseases such as cancer, diabetes and inflammation. Vascular endothelial growth factor (VEGF) family and its receptor system has been shown to be the fundamental regulator in the cell signaling of angiogenesis. Other systems, Angiopoietin-Tie and EphrinB2-Eph4B etc. are also involved in and cooperate with VEGF system to establish the dynamic blood vessel structures. VEGF receptor belongs to PDGF receptor super-gene family, and carries seven Ig-domains in the extracellular region and a tyrosine kinase domain in the intracellular region. Three members of VEGF receptor family, Flt-1, KDR/Flk-1 and Flt-4, have unique characteristics in terms of the signal transduction, and regulate angiogenesis, lymphangiongenesis and vascular permeability. Further studies on VEGF-VEGF receptor system may significantly facilitate our understanding on the physiological as well as pathological vascular systems in the body and the development of new strategies to control and suppress the major diseases in humans.
Topics: Animals; Endothelial Growth Factors; Humans; Lymphokines; Neovascularization, Physiologic; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Structure-Activity Relationship; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 11345501
DOI: 10.1247/csf.26.25 -
The Protein Journal Jun 2023Metamorphic, or fold-switching, proteins feature different folds that are physiologically relevant. The human chemokine XCL1 (or Lymphotactin) is a metamorphic protein...
Metamorphic, or fold-switching, proteins feature different folds that are physiologically relevant. The human chemokine XCL1 (or Lymphotactin) is a metamorphic protein that features two native states, an [Formula: see text] and an all[Formula: see text] fold, which have similar stability at physiological condition. Here, extended molecular dynamics (MD) simulations, principal component analysis of atomic fluctuations and thermodynamic modeling based on both the configurational volume and free energy landscape, are used to obtain a detailed characterization of the conformational thermodynamics of human Lymphotactin and of one of its ancestors (as was previously obtained by genetic reconstruction). Comparison of our computational results with the available experimental data show that the MD-based thermodynamics can explain the experimentally observed variation of the conformational equilibrium between the two proteins. In particular, our computational data provide an interpretation of the thermodynamic evolution in this protein, revealing the relevance of the configurational entropy and of the shape of the free energy landscape within the essential space (i.e., the space defined by the generalized internal coordinates providing the largest, typically non-Gaussian, structural fluctuations).
Topics: Humans; Thermodynamics; Lymphokines; Sialoglycoproteins; Molecular Dynamics Simulation
PubMed: 37233895
DOI: 10.1007/s10930-023-10123-7 -
The American Journal of Pathology Sep 1977Reactions of cell-mediated immunity fall into two broad categories: those that involve direct participation of intact lymphocytes in the effector mechanism of the... (Review)
Review
Reactions of cell-mediated immunity fall into two broad categories: those that involve direct participation of intact lymphocytes in the effector mechanism of the reaction and those that involve mediation by soluble lymphocyte-derived factors known as lymphokines. The first kind of reaction is essentially limited to lymphocyte-dependent cytotoxicity, although certain aspects of T cell-B cell cooperation may fall into this category as well. The second category appears to comprise the bulk of the so-called cell-mediated immune response and provides a link between this system and the inflammatory system. Various lymphokines have been shown to exert profound influence upon inflammatory cell metabolism, cell surface properties, patterns of cell migration, and the activation of cells for various biologic activities involved in host defense. Although substantial information is now available about various physicochemical as well as biologic properties of lymphokines, purification and characterization data are as yet too incomplete to allow us to ascribe all of these activities to discrete mediator molecules. Current work involving the development of antibody-based techniques for mediator assay may shed light on this issue. Information on the kinds of cells capable of lymphokine production is now available. Contrary to prior expectation, T cells are not unique in their capacity for lymphokine production. Under appropriate circumstances, B cells and even nonlymphoid cells can do so as well. The unique property of lymphocytes in this regard appears to relate to their ability to respond to certain specialized signals such as specific antigen or an appropriate mitogen. Mediator production per se may represent a general biologic phenomenon. Although lymphokines have been defined mainly in terms of in vitro assays, early speculations about their in vivo importance are proving correct. Evidence for the role of lymphokines comes from studies involving detection of lymphokines in tissues, studies involving injection of exogenous lymphokines, and studies involving suppression of in vivo reactions by various techniques. The use of antilymphokine antibodies has proven useful in the latter kinds of experiments. Work in many laboratories is beginning to relate these findings to clinically relevant situations. A major unsolved problem relates to the regulation and control of lymphokine production and activity. At present only a limited body of information is available on this point. This is a potentially fruitful area for future investigation since it may provide techniques for manipulating the immune system in ways that are clinically useful.
Topics: Animals; B-Lymphocytes; Cell Membrane; Cell Migration Inhibition; Chemotaxis, Leukocyte; Humans; Immunity, Cellular; Inflammation; Lymphocyte Activation; Lymphokines; Lymphotoxin-alpha; Macrophage Migration-Inhibitory Factors; Macrophages; Mitogens; Neoplasms; Skin Tests; T-Lymphocytes
PubMed: 329682
DOI: No ID Found -
The Journal of Experimental Medicine Apr 1986Northern and dot blotting with a panel of DNA probes were used to monitor the levels of specific mRNAs in mitogen-stimulated human T cells. The induction of IL-2 and IFN...
Northern and dot blotting with a panel of DNA probes were used to monitor the levels of specific mRNAs in mitogen-stimulated human T cells. The induction of IL-2 and IFN mRNAs required the synergistic action of PMA and either PHA or OKT3 mAb. In contrast, several nonlymphokine genes, the protooncogenes c-fos and c-myc, and the IL-2-R gene, were induced by either PHA or PMA alone. PHA increased the background levels of a 70 kD heat shock protein mRNA, but did not affect the observed background of c-myb mRNA. For all mRNAs that were induced, isolated CD4 and CD8 T cell subsets behaved similarly. Exogenous IL-2 had little (IFN) or no (IL-2) effect on lymphokine mRNAs, but significantly increased c-myc, IL-2-R and heat shock protein mRNAs. Therefore, the stimuli for lymphokine mRNAs differed from those required for several inducible nonlymphokine genes. IL-2 and IFN mRNAs exhibited some important similarities with c-myc, however. The levels of IL-2, IFN, and c-myc mRNA followed similar kinetics, peaking at 3 h in restimulated blasts and at 12 h in unstimulated T cells. The subsequent downregulation of lymphokine and c-myc mRNAs was retarded by cycloheximide. The induction of IL-2, IFN, and c-myc mRNAs was blocked by the immunosuppressive drug CsA, but not by the inactive analog CsH, and this block occurred at the level of nuclear transcription. Since the exogenous stimuli for lymphokine and c-myc gene expression differ, we suggest that intracellular controls must be shared to account for the similarities in their kinetics of expression and CsA sensitivity.
Topics: Antibodies, Monoclonal; Cyclosporins; Heat-Shock Proteins; Humans; Kinetics; Lymphokines; Mitogens; Oncogenes; RNA; T-Lymphocytes
PubMed: 2419474
DOI: 10.1084/jem.163.4.922 -
Kidney International Sep 1999Compelling evidence indicates that vascular endothelial growth factor (VEGF) is a fundamental regulator of normal and abnormal angiogenesis. The loss of a single VEGF... (Review)
Review
Compelling evidence indicates that vascular endothelial growth factor (VEGF) is a fundamental regulator of normal and abnormal angiogenesis. The loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF plays also a critical role in kidney development, and its inactivation during early postnatal life results in the suppression of glomerular development and kidney failure. Recent evidence indicates that VEGF is also essential for angiogenesis in the female reproductive tract and for morphogenesis of the epiphyseal growth plate and endochondral bone formation. Substantial experimental evidence also implicates VEGF in pathological angiogenesis. Anti-VEGF monoclonal antibodies or other VEGF inhibitors block the growth of several human tumor cell lines in nude mice. Furthermore, the concentrations of VEGF are elevated in the aqueous and vitreous humors of patients with proliferative retinopathies such as the diabetic retinopathy. In addition, VEGF-induced angiogenesis results in a therapeutic benefit in several animal models of myocardial or limb ischemia. Currently, both therapeutic angiogenesis using recombinant VEGF or VEGF gene transfer and inhibition of VEGF-mediated pathological angiogenesis are being pursued clinically.
Topics: Animals; Cell Differentiation; Cell Transformation, Neoplastic; Endothelial Growth Factors; Female; Gene Expression Regulation; Growth Substances; Hormones; Humans; Lymphokines; Mice; Neoplasms, Experimental; Neovascularization, Pathologic; Neovascularization, Physiologic; Oxygen; Protein Isoforms; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 10469350
DOI: 10.1046/j.1523-1755.1999.00610.x -
The Yale Journal of Biology and Medicine 1987Immunotherapy in the management of neoplastic disease has recently been a major focus of scientific attention. Studies in vitro and in animal systems have provided the... (Review)
Review
Immunotherapy in the management of neoplastic disease has recently been a major focus of scientific attention. Studies in vitro and in animal systems have provided the basis for the first trials of cellular immunotherapy for neoplasia in humans. Work over the past ten years has identified several distinct populations of lymphocytes active in lysing neoplastic cells, including major histocompatibility complex (MHC)-restricted and non-restricted cytotoxic T lymphocytes (CTL), natural killer (NK) cells, the natural cell-mediated cytotoxicity (NCMC) population, and the lymphokine-activated killer (LAK) phenomenon. This paper reviews the current understanding of the distinguishing cell surface phenotypes, recognition structures, mechanisms of neoplastic target cell lysis, activation requirements, and ontogeny of each of these cell groups.
Topics: Animals; Biomarkers, Tumor; Cytotoxicity, Immunologic; Humans; In Vitro Techniques; Killer Cells, Natural; Lymphokines; Neoplasms; T-Lymphocytes, Cytotoxic
PubMed: 3321723
DOI: No ID Found -
The American Journal of Pathology May 1995VPF/VEGF is a multifunctional cytokine that contributes to angiogenesis by both direct and indirect mechanisms. On the one hand, VPF/VEGF stimulates the ECs lining... (Review)
Review
VPF/VEGF is a multifunctional cytokine that contributes to angiogenesis by both direct and indirect mechanisms. On the one hand, VPF/VEGF stimulates the ECs lining nearby microvessels to proliferate, to migrate, and to alter their pattern of gene expression. On the other hand, VPF/VEGF renders these same microvascular ECs hyperpermeable so that they spill plasma proteins into the extravascular space, leading to the clotting of extravasated fibrinogen with deposition of a fibrin gel. Extravascular fibrin serves as a provisional matrix that favors and supports the ingrowth of new blood vessels and other mesenchymal cells that generate mature, vascularized stroma. These same principles apply in tumors, in several examples of non-neoplastic pathology, and in physiological processes that involve angiogenesis and new stroma generation. In all of these examples, microvascular hyperpermeability and the introduction of a provisional, plasma-derived matrix precede and accompany the onset of EC division and new blood vessel formation. It would seem, therefore, that tumors have "borrowed" fundamental mechanisms that developed in multicellular organisms for purposes of tissue defense, renewal, and repair. VPF/VEGF, therefore has taught us something new about angiogenesis; namely, that vascular hyperpermeability and consequent plasma protein extravasation are important, perhaps essential, elements in its generation. However, this finding raises a paradox. While VPF/VEGF induces vascular hyperpermeability, other potent angiogenic factors apparently do not, at least in subtoxic concentrations that are more than sufficient to induce angiogenesis. Nonetheless, wherever angiogenesis has been studied, the newly generated vessels have been found to be hyperpermeable. How, therefore, do angiogenic factors other than VPF/VEGF lead to the formation of new and leaky blood vessels? We do not as yet have a complete answer to this question. One possibility is that at least some angiogenic factors mediate their effect by inducing or stimulating the expression of VPF/VEGF. In fact, there is already one clear example of this. TGF-alpha is a potent angiogenic factor but does not itself increase microvascular permeability. However, TGF-alpha strikingly upregulates VPF/VEGF expression in cultured keratinocytes and is thought to be responsible, at least in part, for the overexpression of VPF/VEGF in psoriasis. Moreover, overexpression of TGF-alpha, along with that of the EGF receptor with which it interacts, is characteristic of many malignant tumors, raising the possibility that TGF-alpha acts to stimulate VPF/VEGF expression in other types of epithelial cells and in this manner induces angiogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Capillary Permeability; Endothelial Growth Factors; Humans; Lymphokines; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 7538264
DOI: No ID Found -
Cancer Treatment Reviews Oct 2013Platelet-derived growth factor-D (PDGF-D) signaling pathway has been reported to be involved in regulating various cellular processes, such as cell growth, apoptotic... (Review)
Review
Platelet-derived growth factor-D (PDGF-D) signaling pathway has been reported to be involved in regulating various cellular processes, such as cell growth, apoptotic cell death, migration, invasion, angiogenesis and metastasis. Recently, multiple studies have shown that PDGF-D plays a critical role in governing epithelial-to-mesenchymal transition (EMT), although the underlying mechanism of PDGF-D-mediated acquisition of EMT is largely unclear. Therefore, this mini review will discuss recent advances in our understanding of the role of PDGF-D in the acquisition of EMT during tumorigenesis. Furthermore, we will summarize the function of chemical inhibitors and natural compounds that are known to inactivate PDGF-D signaling pathway, which leads to the reversal of EMT. In summary, inactivation of PDGF-D could be a novel strategy for achieving better treatment outcome of patients inflicted with cancers.
Topics: Cell Transformation, Neoplastic; Disease Progression; Epithelial-Mesenchymal Transition; Humans; Lymphokines; Platelet-Derived Growth Factor; Signal Transduction
PubMed: 23261166
DOI: 10.1016/j.ctrv.2012.11.006