Leukemia inhibitory factor, a potent cardiac hypertrophic cytokine, activates the JAK/STAT pathway in rat cardiomyocytes.

Leukemia inhibitory factor (LIF) is a member of the interleukin-6 family of cytokines, which induces a wide range of responses in a variety of cells. The aim of this study was to investigate whether LIF induces cardiomyocyte hypertrophy and transmits signals through the JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) pathway in primary cultured neonatal rat cardiomyocytes. LIF increased protein content and [3H]phenylalanine uptake in cardiomyocytes in a dose-dependent manner. LIF (10(3) U/mL) induced rapid tyrosine phosphorylation of gp130, JAK1, JAK2, STAT1, and STAT3 but not Tyk2 or STAT2. LIF also induced autokinase activity of JAK1 in a time-dependent manner. Gel shift assays for interferon gamma activation site/interferon-stimulated responsive element and sis-inducible element (SIE) revealed that LIF induced dimerization of STAT1 and STAT3 and formation of sis-inducing factor complexes, which subsequently interacted with SIE in the promoter. Preincubation with anti-STAT1 and anti-STAT3 antibodies inhibited the binding of SIF complexes. In conclusion, LIF induces cardiac hypertrophy and directly stimulates the JAK/STAT pathway in cardiomyocytes.

[1]  Y. Fujio,et al.  Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes. , 1996, Circulation.

[2]  K. Shiota,et al.  Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[3]  D. Levy,et al.  Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor , 1996, Molecular and cellular biology.

[4]  Austin G Smith,et al.  Essential function of LIF receptor in motor neurons , 1995, Nature.

[5]  B. Klein,et al.  Interleukin‐6 signal transducer gp130 has specific binding sites for different cytokines as determined by antagonistic and agonistic anti‐gp130 monoclonal antibodies , 1995, European journal of immunology.

[6]  J. Ihle.  Cytokine receptor signalling , 1995, Nature.

[7]  S. Rose-John,et al.  A new hepatocyte stimulating factor: cardiotrophin‐1 (CT‐1) , 1995, FEBS letters.

[8]  R. Rees,et al.  Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  G. Fuller,et al.  Interleukin-6 and ciliary neurotrophic factor trigger janus kinase activation and early gene response in rat hepatocytes. , 1995, Gene.

[10]  J. Ihle,et al.  Phosphorylation and Activation of the DNA Binding Activity of Purified Stat1 by the Janus Protein-tyrosine Kinases and the Epidermal Growth Factor Receptor (*) , 1995, The Journal of Biological Chemistry.

[11]  N. Stahl,et al.  STAT3 activation by cytokines utilizing gp130 and related transducers involves a secondary modification requiring an H7-sensitive kinase. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[12]  T. Kishimoto,et al.  Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[13]  W. Wood,et al.  Cardiotrophin-1 , 1995, The Journal of Biological Chemistry.

[14]  G. Stark,et al.  A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin‐6. , 1995, The EMBO journal.

[15]  J. Darnell,et al.  Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors , 1995, Science.

[16]  S. Melmed,et al.  Human and murine pituitary expression of leukemia inhibitory factor. Novel intrapituitary regulation of adrenocorticotropin hormone synthesis and secretion. , 1995, The Journal of clinical investigation.

[17]  D. Levy,et al.  Activation of Acute Phase Response Factor (APRF)/Stat3 Transcription Factor by Growth Hormone (*) , 1995, The Journal of Biological Chemistry.

[18]  K. Chien,et al.  Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[19]  C. Marshall,et al.  Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation , 1995, Cell.

[20]  A. Strasser,et al.  Differential regulation of macrophage differentiation in response to leukemia inhibitory factor/oncostatin-M/interleukin-6: the effect of enforced expression of the SCL transcription factor. , 1995, Blood.

[21]  I. Kerr,et al.  Activation of JAK kinases and STAT proteins by interleukin‐2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. , 1994, The EMBO journal.

[22]  K. Feingold,et al.  Leukemia inhibitory factor induces changes in lipid metabolism in cultured adipocytes. , 1994, Endocrinology.

[23]  G. Yancopoulos,et al.  Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. , 1994, The Journal of biological chemistry.

[24]  O. Silvennoinen,et al.  Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S. Dower,et al.  Oncostatin M and leukemia inhibitory factor trigger overlapping and different signals through partially shared receptor complexes. , 1994, The Journal of biological chemistry.

[26]  S. Akira,et al.  Cytokine signal transduction , 1994, Cell.

[27]  G. Yancopoulos,et al.  Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. , 1994, Science.

[28]  C. Schindler,et al.  Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. , 1994, Science.

[29]  D. Friend,et al.  Multiple regions within the cytoplasmic domains of the leukemia inhibitory factor receptor and gp130 cooperate in signal transduction in hepatic and neuronal cells , 1994, Molecular and cellular biology.

[30]  J. Darnell,et al.  A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. , 1993, Science.

[31]  J. Darnell,et al.  A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. , 1993, Science.

[32]  P. Brûlet,et al.  Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation , 1993, Nature.

[33]  S. Ziegler,et al.  Reconstitution of the response to leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in hepatoma cells. , 1993, The Journal of biological chemistry.

[34]  J. Darnell,et al.  Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. , 1992, Science.

[35]  S. Burstein,et al.  Leukemia inhibitory factor and interleukin‐11 promote maturation of murine and human megakaryocytes in vitro , 1992, Journal of cellular physiology.

[36]  David J. Anderson,et al.  CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130 , 1992, Cell.

[37]  Comeau,et al.  The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. , 1992, Science.

[38]  C. Thut,et al.  Leukemia inhibitory factor receptor is structurally related to the IL‐6 signal transducer, gp130. , 1991, The EMBO journal.

[39]  D. Hilton,et al.  Leukemia inhibitory factor can potentiate murine megakaryocyte production in vitro. , 1991, Blood.

[40]  Melvin I. Simon,et al.  Diversity of G proteins in signal transduction , 1991, Science.

[41]  T. Decker,et al.  Cytoplasmic activation of GAF, an IFN‐gamma‐regulated DNA‐binding factor. , 1991, The EMBO journal.

[42]  D. Metcalf.  The leukemia inhibitory factor (LIF). , 1991, International journal of cell cloning.

[43]  T. Parker,et al.  Peptide growth factors can provoke "fetal" contractile protein gene expression in rat cardiac myocytes. , 1990, The Journal of clinical investigation.

[44]  R. Aebersold,et al.  The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor. , 1989, Science.

[45]  R. Fandrich,et al.  Basic fibroblast growth factor in atria and ventricles of the vertebrate heart , 1989, The Journal of cell biology.

[46]  K. Chien,et al.  Cardiovascular Molecular Biology: Introduction to the Series , 1989, Circulation.

[47]  J. Moreau,et al.  Leukaemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cells , 1988, Nature.

[48]  Donald Metcalf,et al.  Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells , 1988, Nature.

[49]  D. Hilton,et al.  Specific binding of murine leukemia inhibitory factor to normal and leukemic monocytic cells. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[50]  B. Cochran,et al.  Inducible binding of a factor to the c-fos regulatory region. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[51]  K. Fukada.  Purification and partial characterization of a cholinergic neuronal differentiation factor. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[52]  P. Simpson,et al.  Stimulation of hypertrophy of cultured neonatal rat heart cells through an alpha 1-adrenergic receptor and induction of beating through an alpha 1- and beta 1-adrenergic receptor interaction. Evidence for independent regulation of growth and beating. , 1985, Circulation research.

[53]  R. Roeder,et al.  Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. , 1983, Nucleic acids research.

[54]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.