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. 1995 May 23;92(11):4862–4866. doi: 10.1073/pnas.92.11.4862

Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice.

H Hirota 1, K Yoshida 1, T Kishimoto 1, T Taga 1
PMCID: PMC41807  PMID: 7539136

Abstract

To investigate the physiological roles of gp130 in detail and to determine the pathological consequence of abnormal activation of gp130, transgenic mice having continuously activated gp130 were created. This was carried out by mating mice from interleukin 6 (IL-6) and IL-6 receptor (IL-6R) transgenic lines. Offspring overexpressing both IL-6 and IL-6R showed constitutive tyrosine phosphorylation of gp130 and a downstream signaling molecule, acute phase response factor/signal transducer and activator of transcription 3. Surprisingly, the distinguishing feature of such offspring was hypertrophy of ventricular myocardium and consequent thickened ventricular walls of the heart, where gp130 is also expressed, in adulthood. Transgenic mice overexpressing either IL-6 or IL-6R alone did not show detectable myocardial abnormalities. Neonatal heart muscle cells from normal mice, when cultured in vitro, enlarged in response to a combination of IL-6 and a soluble form of IL-6R. The results suggest that activation of the gp130 signaling pathways leads to cardiac hypertrophy and that these signals might be involved in physiological regulation of myocardium.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akira S., Nishio Y., Inoue M., Wang X. J., Wei S., Matsusaka T., Yoshida K., Sudo T., Naruto M., Kishimoto T. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. 1994 Apr 8;77(1):63–71. doi: 10.1016/0092-8674(94)90235-6. [DOI] [PubMed] [Google Scholar]
  2. Bachmann S., Peters J., Engler E., Ganten D., Mullins J. Transgenic rats carrying the mouse renin gene--morphological characterization of a low-renin hypertension model. Kidney Int. 1992 Jan;41(1):24–36. doi: 10.1038/ki.1992.4. [DOI] [PubMed] [Google Scholar]
  3. Bajusz E. Hereditary cardiomyopathy: a new disease model. Am Heart J. 1969 May;77(5):686–696. doi: 10.1016/0002-8703(69)90556-0. [DOI] [PubMed] [Google Scholar]
  4. Capasso J. M., Olivetti G., Anversa P. Mechanical and electrical properties of cardiomyopathic hearts of Syrian hamsters. Am J Physiol. 1989 Dec;257(6 Pt 2):H1836–H1842. doi: 10.1152/ajpheart.1989.257.6.H1836. [DOI] [PubMed] [Google Scholar]
  5. Davis S., Aldrich T. H., Stahl N., Pan L., Taga T., Kishimoto T., Ip N. Y., Yancopoulos G. D. LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science. 1993 Jun 18;260(5115):1805–1808. doi: 10.1126/science.8390097. [DOI] [PubMed] [Google Scholar]
  6. Fattori E., Della Rocca C., Costa P., Giorgio M., Dente B., Pozzi L., Ciliberto G. Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood. 1994 May 1;83(9):2570–2579. [PubMed] [Google Scholar]
  7. Finkel M. S., Oddis C. V., Jacob T. D., Watkins S. C., Hattler B. G., Simmons R. L. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science. 1992 Jul 17;257(5068):387–389. doi: 10.1126/science.1631560. [DOI] [PubMed] [Google Scholar]
  8. Gearing D. P., Comeau M. R., Friend D. J., Gimpel S. D., Thut C. J., McGourty J., Brasher K. K., King J. A., Gillis S., Mosley B. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science. 1992 Mar 13;255(5050):1434–1437. doi: 10.1126/science.1542794. [DOI] [PubMed] [Google Scholar]
  9. Hibi M., Murakami M., Saito M., Hirano T., Taga T., Kishimoto T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990 Dec 21;63(6):1149–1157. doi: 10.1016/0092-8674(90)90411-7. [DOI] [PubMed] [Google Scholar]
  10. Hilton D. J., Gough N. M. Leukemia inhibitory factor: a biological perspective. J Cell Biochem. 1991 May;46(1):21–26. doi: 10.1002/jcb.240460105. [DOI] [PubMed] [Google Scholar]
  11. Hirata Y., Taga T., Hibi M., Nakano N., Hirano T., Kishimoto T. Characterization of IL-6 receptor expression by monoclonal and polyclonal antibodies. J Immunol. 1989 Nov 1;143(9):2900–2906. [PubMed] [Google Scholar]
  12. Honda M., Yamamoto S., Cheng M., Yasukawa K., Suzuki H., Saito T., Osugi Y., Tokunaga T., Kishimoto T. Human soluble IL-6 receptor: its detection and enhanced release by HIV infection. J Immunol. 1992 Apr 1;148(7):2175–2180. [PubMed] [Google Scholar]
  13. Horiuchi M., Yoshida H., Kobayashi K., Kuriwaki K., Yoshimine K., Tomomura M., Koizumi T., Nikaido H., Hayakawa J., Kuwajima M. Cardiac hypertrophy in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency. FEBS Lett. 1993 Jul 12;326(1-3):267–271. doi: 10.1016/0014-5793(93)81805-a. [DOI] [PubMed] [Google Scholar]
  14. Ip N. Y., Nye S. H., Boulton T. G., Davis S., Taga T., Li Y., Birren S. J., Yasukawa K., Kishimoto T., Anderson D. J. CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130. Cell. 1992 Jun 26;69(7):1121–1132. doi: 10.1016/0092-8674(92)90634-o. [DOI] [PubMed] [Google Scholar]
  15. Iwaki K., Sukhatme V. P., Shubeita H. E., Chien K. R. Alpha- and beta-adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. fos/jun expression is associated with sarcomere assembly; Egr-1 induction is primarily an alpha 1-mediated response. J Biol Chem. 1990 Aug 15;265(23):13809–13817. [PubMed] [Google Scholar]
  16. Kinugawa K., Takahashi T., Kohmoto O., Yao A., Aoyagi T., Momomura S., Hirata Y., Serizawa T. Nitric oxide-mediated effects of interleukin-6 on [Ca2+]i and cell contraction in cultured chick ventricular myocytes. Circ Res. 1994 Aug;75(2):285–295. doi: 10.1161/01.res.75.2.285. [DOI] [PubMed] [Google Scholar]
  17. Kishimoto T., Akira S., Taga T. Interleukin-6 and its receptor: a paradigm for cytokines. Science. 1992 Oct 23;258(5082):593–597. doi: 10.1126/science.1411569. [DOI] [PubMed] [Google Scholar]
  18. Kishimoto T., Taga T., Akira S. Cytokine signal transduction. Cell. 1994 Jan 28;76(2):253–262. doi: 10.1016/0092-8674(94)90333-6. [DOI] [PubMed] [Google Scholar]
  19. Lee H. R., Henderson S. A., Reynolds R., Dunnmon P., Yuan D., Chien K. R. Alpha 1-adrenergic stimulation of cardiac gene transcription in neonatal rat myocardial cells. Effects on myosin light chain-2 gene expression. J Biol Chem. 1988 May 25;263(15):7352–7358. [PubMed] [Google Scholar]
  20. Lütticken C., Wegenka U. M., Yuan J., Buschmann J., Schindler C., Ziemiecki A., Harpur A. G., Wilks A. F., Yasukawa K., Taga T. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science. 1994 Jan 7;263(5143):89–92. doi: 10.1126/science.8272872. [DOI] [PubMed] [Google Scholar]
  21. Metcalf D., Gearing D. P. Fatal syndrome in mice engrafted with cells producing high levels of the leukemia inhibitory factor. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5948–5952. doi: 10.1073/pnas.86.15.5948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Metcalf D., Nicola N. A., Gearing D. P. Effects of injected leukemia inhibitory factor on hematopoietic and other tissues in mice. Blood. 1990 Jul 1;76(1):50–56. [PubMed] [Google Scholar]
  23. Murakami M., Hibi M., Nakagawa N., Nakagawa T., Yasukawa K., Yamanishi K., Taga T., Kishimoto T. IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science. 1993 Jun 18;260(5115):1808–1810. doi: 10.1126/science.8511589. [DOI] [PubMed] [Google Scholar]
  24. Narazaki M., Witthuhn B. A., Yoshida K., Silvennoinen O., Yasukawa K., Ihle J. N., Kishimoto T., Taga T. Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2285–2289. doi: 10.1073/pnas.91.6.2285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Narazaki M., Yasukawa K., Saito T., Ohsugi Y., Fukui H., Koishihara Y., Yancopoulos G. D., Taga T., Kishimoto T. Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood. 1993 Aug 15;82(4):1120–1126. [PubMed] [Google Scholar]
  26. Niwa H., Yamamura K., Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene. 1991 Dec 15;108(2):193–199. doi: 10.1016/0378-1119(91)90434-d. [DOI] [PubMed] [Google Scholar]
  27. Ooshima A., Yamori Y., Okamoto K. Cardiovascular lesions in the selectively-bred group of spontaneously hypertensive rats with severe hypertension. Jpn Circ J. 1972 Aug;36(8):797–812. doi: 10.1253/jcj.36.797. [DOI] [PubMed] [Google Scholar]
  28. Pennica D., King K. L., Shaw K. J., Luis E., Rullamas J., Luoh S. M., Darbonne W. C., Knutzon D. S., Yen R., Chien K. R. Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1142–1146. doi: 10.1073/pnas.92.4.1142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Saito M., Yoshida K., Hibi M., Taga T., Kishimoto T. Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J Immunol. 1992 Jun 15;148(12):4066–4071. [PubMed] [Google Scholar]
  30. Saito T., Yasukawa K., Suzuki H., Futatsugi K., Fukunaga T., Yokomizo C., Koishihara Y., Fukui H., Ohsugi Y., Yawata H. Preparation of soluble murine IL-6 receptor and anti-murine IL-6 receptor antibodies. J Immunol. 1991 Jul 1;147(1):168–173. [PubMed] [Google Scholar]
  31. Shen M. M., Skoda R. C., Cardiff R. D., Campos-Torres J., Leder P., Ornitz D. M. Expression of LIF in transgenic mice results in altered thymic epithelium and apparent interconversion of thymic and lymph node morphologies. EMBO J. 1994 Mar 15;13(6):1375–1385. doi: 10.1002/j.1460-2075.1994.tb06391.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Shoki M., Kawaguchi H., Okamoto H., Sano H., Sawa H., Kudo T., Hirao N., Sakata Y., Yasuda H. Phosphatidylinositol and inositolphosphatide metabolism in hypertrophied rat heart. Jpn Circ J. 1992 Feb;56(2):142–147. doi: 10.1253/jcj.56.142. [DOI] [PubMed] [Google Scholar]
  33. Shubeita H. E., McDonough P. M., Harris A. N., Knowlton K. U., Glembotski C. C., Brown J. H., Chien K. R. Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes. A paracrine mechanism for myocardial cell hypertrophy. J Biol Chem. 1990 Nov 25;265(33):20555–20562. [PubMed] [Google Scholar]
  34. Simpson P. 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. Circ Res. 1985 Jun;56(6):884–894. doi: 10.1161/01.res.56.6.884. [DOI] [PubMed] [Google Scholar]
  35. Stahl N., Boulton T. G., Farruggella T., Ip N. Y., Davis S., Witthuhn B. A., Quelle F. W., Silvennoinen O., Barbieri G., Pellegrini S. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science. 1994 Jan 7;263(5143):92–95. doi: 10.1126/science.8272873. [DOI] [PubMed] [Google Scholar]
  36. Suematsu S., Matsuda T., Aozasa K., Akira S., Nakano N., Ohno S., Miyazaki J., Yamamura K., Hirano T., Kishimoto T. IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7547–7551. doi: 10.1073/pnas.86.19.7547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Suematsu S., Matsusaka T., Matsuda T., Ohno S., Miyazaki J., Yamamura K., Hirano T., Kishimoto T. Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):232–235. doi: 10.1073/pnas.89.1.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Suzuki H., Yasukawa K., Saito T., Narazaki M., Hasegawa A., Taga T., Kishimoto T. Serum soluble interleukin-6 receptor in MRL/lpr mice is elevated with age and mediates the interleukin-6 signal. Eur J Immunol. 1993 May;23(5):1078–1082. doi: 10.1002/eji.1830230515. [DOI] [PubMed] [Google Scholar]
  39. Taga T., Hibi M., Hirata Y., Yamasaki K., Yasukawa K., Matsuda T., Hirano T., Kishimoto T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989 Aug 11;58(3):573–581. doi: 10.1016/0092-8674(89)90438-8. [DOI] [PubMed] [Google Scholar]
  40. Taga T., Kishimoto T. Cytokine receptors and signal transduction. FASEB J. 1992 Dec;6(15):3387–3396. doi: 10.1096/fasebj.6.15.1334470. [DOI] [PubMed] [Google Scholar]
  41. Taga T., Narazaki M., Yasukawa K., Saito T., Miki D., Hamaguchi M., Davis S., Shoyab M., Yancopoulos G. D., Kishimoto T. Functional inhibition of hematopoietic and neurotrophic cytokines by blocking the interleukin 6 signal transducer gp130. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10998–11001. doi: 10.1073/pnas.89.22.10998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tamura T., Udagawa N., Takahashi N., Miyaura C., Tanaka S., Yamada Y., Koishihara Y., Ohsugi Y., Kumaki K., Taga T. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11924–11928. doi: 10.1073/pnas.90.24.11924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yamamura K., Kikutani H., Takahashi N., Taga T., Akira S., Kawai K., Fukuchi K., Kumahara Y., Honjo T., Kishimoto T. Introduction of human gamma 1 immunoglobulin genes into fertilized mouse eggs. J Biochem. 1984 Aug;96(2):357–363. doi: 10.1093/oxfordjournals.jbchem.a134845. [DOI] [PubMed] [Google Scholar]
  44. Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B., Taniguchi T., Hirano T., Kishimoto T. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science. 1988 Aug 12;241(4867):825–828. doi: 10.1126/science.3136546. [DOI] [PubMed] [Google Scholar]
  45. Yasukawa K., Saito T., Fukunaga T., Sekimori Y., Koishihara Y., Fukui H., Ohsugi Y., Matsuda T., Yawata H., Hirano T. Purification and characterization of soluble human IL-6 receptor expressed in CHO cells. J Biochem. 1990 Oct;108(4):673–676. doi: 10.1093/oxfordjournals.jbchem.a123261. [DOI] [PubMed] [Google Scholar]
  46. Yin T., Taga T., Tsang M. L., Yasukawa K., Kishimoto T., Yang Y. C. Involvement of IL-6 signal transducer gp130 in IL-11-mediated signal transduction. J Immunol. 1993 Sep 1;151(5):2555–2561. [PubMed] [Google Scholar]
  47. Yoshida K., Chambers I., Nichols J., Smith A., Saito M., Yasukawa K., Shoyab M., Taga T., Kishimoto T. Maintenance of the pluripotential phenotype of embryonic stem cells through direct activation of gp130 signalling pathways. Mech Dev. 1994 Feb;45(2):163–171. doi: 10.1016/0925-4773(94)90030-2. [DOI] [PubMed] [Google Scholar]
  48. Zhong Z., Wen Z., Darnell J. E., Jr Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994 Apr 1;264(5155):95–98. doi: 10.1126/science.8140422. [DOI] [PubMed] [Google Scholar]
  49. Zhu H., Garcia A. V., Ross R. S., Evans S. M., Chien K. R. A conserved 28-base-pair element (HF-1) in the rat cardiac myosin light-chain-2 gene confers cardiac-specific and alpha-adrenergic-inducible expression in cultured neonatal rat myocardial cells. Mol Cell Biol. 1991 Apr;11(4):2273–2281. doi: 10.1128/mcb.11.4.2273. [DOI] [PMC free article] [PubMed] [Google Scholar]

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