(Circulation. 1996;94:2626-2632.)
© 1996 American Heart Association, Inc.
Articles |
Activation of JAK-STAT and MAP Kinases by Leukemia Inhibitory Factor Through gp130 in Cardiac Myocytes
Department of Medicine III, Osaka University Medical School, Japan.
Correspondence to Keiko Yamauchi-Takihara, MD, PhD, Department of Medicine III, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan. E-mail takihara@imed3.med.osaka-u.ac.jp.
Background Interleukin (IL)-6–related cytokines share gp130 as the signal-transducing protein. Downstream of gp130, two signal-transducing pathways have been recognized, the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway and the Ras–mitogen-activated protein kinase (MAPK) pathway. To determine whether these two signaling pathways through gp130 are present in cardiac myocytes, we examined their activation by using leukemia inhibitory factor (LIF), which is a member of the IL-6 cytokine family.
Methods and Results Lysates from neonatal rat cardiac myocytes were immunoprecipitated with anti-gp130, anti-JAK1, or anti-STAT3 antibody and blotted with anti-phosphotyrosine antibody. Tyrosine phosphorylation of gp130, JAK1, and STAT3 was observed after LIF stimulation in cardiac myocytes. MAPKs were maximally activated 5 minutes after LIF stimulation. Furthermore, anti-gp130 antibody significantly inhibited the LIF-induced activation of JAK1, STAT3, and MAPKs. To examine whether these signaling pathways were also activated in the adult heart in vivo, LIF was injected intravenously into a 6-week-old mouse, and the heart was examined subsequently. gp130, STAT3, and MAPKs were activated in the heart after LIF treatment.
Conclusions These results demonstrate for the first time that a JAK-STAT pathway and a MAPK pathway are present downstream of gp130 in cardiac myocytes and are rapidly activated by LIF both in vitro and in vivo. Activation of gp130 constitutes a novel signaling pathway in cardiac myocytes.
Key Words: signal transduction • hypertrophy • interleukins • gp130
This article has been cited by other articles:
 |
|
 |
|
  T. Ichiki, M. Jougasaki, M. Setoguchi, J. Imamura, H. Nakashima, T. Matsuoka, M. Sonoda, K. Nakamura, S. Minagoe, and C. Tei Cardiotrophin-1 stimulates intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in human aortic endothelial cells Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H750 - H763. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-T. Tsai, L.-P. Lai, K.-T. Kuo, J.-J. Hwang, C.-S. Hsieh, K.-L. Hsu, C.-D. Tseng, Y.-Z. Tseng, F.-T. Chiang, and J.-L. Lin Angiotensin II Activates Signal Transducer and Activators of Transcription 3 via Rac1 in Atrial Myocytes and Fibroblasts: Implication for the Therapeutic Effect of Statin in Atrial Structural Remodeling Circulation, January 22, 2008; 117(3): 344 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Hamilton, L. Lin, Y. Wang, and A. A. Knowlton Effect of ovariectomy on cardiac gene expression: inflammation and changes in SOCS gene expression Physiol Genomics, January 17, 2008; 32(2): 254 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Magni, E. Dozio, M. Ruscica, H. Watanobe, A. Cariboni, R. Zaninetti, M. Motta, and R. Maggi Leukemia Inhibitory Factor Induces the Chemomigration of Immortalized Gonadotropin-Releasing Hormone Neurons through the Independent Activation of the Janus Kinase/Signal Transducer and Activator of Transcription 3, Mitogen-Activated Protein Kinase/Extracellularly Regulated Kinase 1/2, and Phosphatidylinositol 3-Kinase/Akt Signaling Pathways Mol. Endocrinol., May 1, 2007; 21(5): 1163 - 1174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Trenerry, K. A. Carey, A. C. Ward, and D. Cameron-Smith STAT3 signaling is activated in human skeletal muscle following acute resistance exercise J Appl Physiol, April 1, 2007; 102(4): 1483 - 1489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yano, R. Ozono, Y. Oishi, M. Kambe, M. Yoshizumi, T. Ishida, S. Omura, T. Oshima, and K. Igarashi Genetic ablation of the transcription repressor Bach1 leads to myocardial protection against ischemia/reperfusion in mice. Genes Cells, July 1, 2006; 11(7): 791 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Mohri, Y. Fujio, M. Maeda, T. Ito, T. Iwakura, Y. Oshima, Y. Uozumi, M. Segawa, H. Yamamoto, T. Kishimoto, et al. Leukemia Inhibitory Factor Induces Endothelial Differentiation in Cardiac Stem Cells J. Biol. Chem., March 10, 2006; 281(10): 6442 - 6447. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Coles, C. Boscarino, M. Takahashi, D. Grant, A. Chang, J. Ritter, X. Dai, C. Du, G. Musso, H. Yamabi, et al. Cardioprotective stress response in the human fetal heart J. Thorac. Cardiovasc. Surg., May 1, 2005; 129(5): 1128 - 1136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Casey, P. G. Arthur, and M. A. Bogoyevitch Proteomic Analysis Reveals Different Protein Changes during Endothelin-1- or Leukemic Inhibitory Factor-induced Hypertrophy of Cardiomyocytes in Vitro Mol. Cell. Proteomics, May 1, 2005; 4(5): 651 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Berry, T. J. Pirolli, V. Jayasankar, K. J. Morine, M. A. Moise, O. Fisher, T. J. Gardner, P. H. Patterson, and Y. J. Woo Targeted overexpression of leukemia inhibitory factor to preserve myocardium in a rat model of postinfarction heart failure J. Thorac. Cardiovasc. Surg., December 1, 2004; 128(6): 866 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Bachetti, L. Comini, E. Pasini, and R. Ferrari Anti-cytokine therapy in chronic heart failure: new approaches and unmet promises Eur. Heart J. Suppl., November 1, 2004; 6(suppl_F): F16 - F21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Smith, N. Suleman, L. Lacerda, L. H. Opie, S. Akira, K. R. Chien, and M. N. Sack Genetic depletion of cardiac myocyte STAT-3 abolishes classical preconditioning Cardiovasc Res, September 1, 2004; 63(4): 611 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Takahashi, K. Fukuda, S. Miyoshi, M. Murata, T. Kato, M. Ita, T. Tanabe, and S. Ogawa Leukemia Inhibitory Factor Activates Cardiac L-Type Ca2+ Channels via Phosphorylation of Serine 1829 in the Rabbit Cav1.2 Subunit Circ. Res., May 14, 2004; 94(9): 1242 - 1248. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S Roffman High-Versus Low-Dose ACE Inhibitor Therapy in Chronic Heart Failure Ann. Pharmacother., May 1, 2004; 38(5): 831 - 838. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W Weiss, W. S Speidl, C. Kaun, G. Rega, C. Springer, K. Macfelda, U. M Losert, S. L Grant, M. L Marro, A. D Rhodes, et al. Glycoprotein 130 ligand oncostatin-M induces expression of vascular endothelial growth factor in human adult cardiac myocytes Cardiovasc Res, September 1, 2003; 59(3): 628 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Nakaoka, K. Nishida, Y. Fujio, M. Izumi, K. Terai, Y. Oshima, S. Sugiyama, S. Matsuda, S. Koyasu, K. Yamauchi-Takihara, et al. Activation of gp130 Transduces Hypertrophic Signal Through Interaction of Scaffolding/Docking Protein Gab1 With Tyrosine Phosphatase SHP2 in Cardiomyocytes Circ. Res., August 8, 2003; 93(3): 221 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Yu, R. H. Kennedy, and S. J. Liu JAK2/STAT3, Not ERK1/2, Mediates Interleukin-6-induced Activation of Inducible Nitric-oxide Synthase and Decrease in Contractility of Adult Ventricular Myocytes J. Biol. Chem., April 25, 2003; 278(18): 16304 - 16309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Jougasaki, H. Leskinen, A. M. Larsen, A. Cataliotti, H. H. Chen, and J. C. Burnett Jr. Leukemia inhibitory factor is augmented in the heart in experimental heart failure Eur J Heart Fail, March 1, 2003; 5(2): 137 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C.H Ng, N. W Court, C. G dos Remedios, and M. A Bogoyevitch Activation of signal transducer and activator of transcription (STAT) pathways in failing human hearts Cardiovasc Res, February 1, 2003; 57(2): 333 - 346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Sirera, A. Salvador, I. Roldan, R. Talens, A. Gonzalez-Molina, and M. Rivera Quantification of proinflammatory cytokines in the urine of congestive heart failure patients. Its relationship with plasma levels Eur J Heart Fail, January 1, 2003; 5(1): 27 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kunisada, E. Tone, S. Negoro, Y. Nakaoka, Y. Oshima, T. Osugi, M. Funamoto, M. Izumi, Y. Fujio, H. Hirota, et al. Bcl-xl reduces doxorubicin-induced myocardial damage but fails to control cardiac gene downregulation Cardiovasc Res, March 1, 2002; 53(4): 936 - 943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Osugi, Y. Oshima, Y. Fujio, M. Funamoto, A. Yamashita, S. Negoro, K. Kunisada, M. Izumi, Y. Nakaoka, H. Hirota, et al. Cardiac-specific Activation of Signal Transducer and Activator of Transcription 3 Promotes Vascular Formation in the Heart J. Biol. Chem., February 15, 2002; 277(8): 6676 - 6681. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-T. Xuan, Y. Guo, H. Han, Y. Zhu, and R. Bolli An essential role of the JAK-STAT pathway in ischemic preconditioning PNAS, July 31, 2001; 98(16): 9050 - 9055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ueda, T. Nakamura, K. Matsumoto, Y. Sawa, H. Matsuda, and T. Nakamura A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats Cardiovasc Res, July 1, 2001; 51(1): 41 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kato, M. Sano, S. Miyoshi, T. Sato, D. Hakuno, H. Ishida, H. Kinoshita-Nakazawa, K. Fukuda, and S. Ogawa Calmodulin Kinases II and IV and Calcineurin Are Involved in Leukemia Inhibitory Factor-Induced Cardiac Hypertrophy in Rats Circ. Res., November 10, 2000; 87(10): 937 - 945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kodama, K. Fukuda, J. Pan, M. Sano, T. Takahashi, T. Kato, S. Makino, T. Manabe, M. Murata, and S. Ogawa Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1635 - H1644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Negoro, K. Kunisada, E. Tone, M. Funamoto, H. Oh, T. Kishimoto, and K. Yamauchi-Takihara Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction Cardiovasc Res, September 1, 2000; 47(4): 797 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ruwhof and A. van der Laarse Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways Cardiovasc Res, July 1, 2000; 47(1): 23 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Auernhammer and S. Melmed Leukemia-Inhibitory Factor--Neuroimmune Modulator of Endocrine Function Endocr. Rev., June 1, 2000; 21(3): 313 - 345. [Abstract] [Full Text]
|
|
|
|
 |
|
 B. Gloss, S. Villegas, F. J. Villarreal, A. Moriscot, and W. H. Dillmann Thyroid hormone-induced stimulation of the sarcoplasmic reticulum Ca2+ ATPase gene is inhibited by LIF and IL-6 Am J Physiol Endocrinol Metab, April 1, 2000; 278(4): E738 - E743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Funamoto, Y. Fujio, K. Kunisada, S. Negoro, E. Tone, T. Osugi, H. Hirota, M. Izumi, K. Yoshizaki, K. Walsh, et al. Signal Transducer and Activator of Transcription 3 Is Required for Glycoprotein 130-mediated Induction of Vascular Endothelial Growth Factor in Cardiac Myocytes J. Biol. Chem., March 31, 2000; 275(14): 10561 - 10566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Bogoyevitch Signalling via stress-activated mitogen-activated protein kinases in the cardiovascular system Cardiovasc Res, March 1, 2000; 45(4): 826 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Damas, L. Gullestad, T. Ueland, N. O. Solum, S. Simonsen, S. S Froland, and P. Aukrust CXC-chemokines, a new group of cytokines in congestive heart failure -- possible role of platelets and monocytes Cardiovasc Res, January 14, 2000; 45(2): 428 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kunisada, S. Negoro, E. Tone, M. Funamoto, T. Osugi, S. Yamada, M. Okabe, T. Kishimoto, and K. Yamauchi-Takihara Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy PNAS, January 4, 2000; 97(1): 315 - 319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Gullestad, P.a. Aukrust, T. Ueland, T. Espevik, G. Yee, R. Vagelos, S. S. Froland, and M. Fowler Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure J. Am. Coll. Cardiol., December 1, 1999; 34(7): 2061 - 2067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Takahashi, K. Fukuda, J. Pan, H. Kodama, M. Sano, S. Makino, T. Kato, T. Manabe, and S. Ogawa Characterization of Insulin-Like Growth Factor-1-Induced Activation of the JAK/STAT Pathway in Rat Cardiomyocytes Circ. Res., November 12, 1999; 85(10): 884 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Kim, T. Lee, J. Fu, and M. E. Ritchie Characterization of MAP kinase and PKC isoform and effect of ACE inhibition in hypertrophy in vivo Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1808 - H1816. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Pan, K. Fukuda, M. Saito, J. Matsuzaki, H. Kodama, M. Sano, T. Takahashi, T. Kato, and S. Ogawa Mechanical Stretch Activates the JAK/STAT Pathway in Rat Cardiomyocytes Circ. Res., May 28, 1999; 84(10): 1127 - 1136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang and S. W. Halvorsen Reciprocal Regulation of Ciliary Neurotrophic Factor Receptors and Acetylcholine Receptors during Synaptogenesis in Embryonic Chick Atria J. Neurosci., September 15, 1998; 18(18): 7372 - 7380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kunisada, E. Tone, Y. Fujio, H. Matsui, K. Yamauchi-Takihara, and T. Kishimoto Activation of gp130 Transduces Hypertrophic Signals via STAT3 in Cardiac Myocytes Circulation, July 28, 1998; 98(4): 346 - 352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Oh, Y. Fujio, K. Kunisada, H. Hirota, H. Matsui, T. Kishimoto, and K. Yamauchi-Takihara Activation of Phosphatidylinositol 3-Kinase through Glycoprotein 130 Induces Protein Kinase B and p70 S6 Kinase Phosphorylation in Cardiac Myocytes J. Biol. Chem., April 17, 1998; 273(16): 9703 - 9710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Servidei, Y. Aoki, S. E. Lewis, A. Symes, J. S. Fink, and S. A. Reeves Coordinate Regulation of STAT Signaling and c-fos Expression by the Tyrosine Phosphatase SHP-2 J. Biol. Chem., March 13, 1998; 273(11): 6233 - 6241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sumida, S. Umemura, K. Tamura, M. Kihara, S.-i. Kobayashi, T. Ishigami, M. Yabana, N. Nyui, H. Ochiai, A. Fukamizu, et al. Increased Cardiac Angiotensin II Receptors in Angiotensinogen-Deficient Mice Hypertension, January 1, 1998; 31(1): 45 - 49. [Abstract] [Full Text]
|
|
|
|
|
|
M. van Bilsen Signal transduction revisited: recent developments in angiotensin II signaling in the cardiovascular system Cardiovasc Res, December 1, 1997; 36(3): 310 - 322. [Full Text] [PDF]
|
|
|
|
|
|
H. Kodama, K. Fukuda, J. Pan, S. Makino, A. Baba, S. Hori, and S. Ogawa Leukemia Inhibitory Factor, a Potent Cardiac Hypertrophic Cytokine, Activates the JAK/STAT Pathway in Rat Cardiomyocytes Circ. Res., November 19, 1997; 81(5): 656 - 663. [Abstract] [Full Text]
|
|
|
|
|
|
J. Pan, K. Fukuda, H. Kodama, S. Makino, T. Takahashi, M. Sano, S. Hori, and S. Ogawa Role of Angiotensin II in Activation of the JAK/STAT Pathway Induced by Acute Pressure Overload in the Rat Heart Circ. Res., October 19, 1997; 81(4): 611 - 617. [Abstract] [Full Text]
|
|
|
|
|
|
R. A. Kelly and T. W. Smith de Modulatione Cordis Circulation, November 15, 1996; 94(10): 2361 - 2363. [Full Text]
|
|
|
|
|
|
M. Sano, K. Fukuda, H. Kodama, J. Pan, M. Saito, J. Matsuzaki, T. Takahashi, S. Makino, T. Kato, and S. Ogawa Interleukin-6 Family of Cytokines Mediate Angiotensin II-induced Cardiac Hypertrophy in Rodent Cardiomyocytes J. Biol. Chem., September 15, 2000; 275(38): 29717 - 29723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. H. Ng, C. S. Long, and M. A. Bogoyevitch A Role for the Extracellular Signal-regulated Kinase and p38 Mitogen-activated Protein Kinases in Interleukin-1beta -stimulated Delayed Signal Tranducer and Activator of Transcription 3 Activation, Atrial Natriuretic Factor Expression, and Cardiac Myocyte Morphology J. Biol. Chem., July 27, 2001; 276(31): 29490 - 29498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Izumi, Y. Fujio, K. Kunisada, S. Negoro, E. Tone, M. Funamoto, T. Osugi, Y. Oshima, Y. Nakaoka, T. Kishimoto, et al. Bone Morphogenetic Protein-2 Inhibits Serum Deprivation-induced Apoptosis of Neonatal Cardiac Myocytes through Activation of the Smad1 Pathway J. Biol. Chem., August 10, 2001; 276(33): 31133 - 31141. [Abstract] [Full Text] [PDF]
|
|