Abstract
The effect of differential signalling by IL-6 and leukaemia inhibitory factor (LIF) which signal by gp130 homodimerisation or LIFRβ/gp130 heterodimerisation on survival and hypertrophy was studied in neonatal rat cardiomyocytes. Both LIF and IL-6 [in the absence of soluble IL-6 receptor (sIL-6Rα)] activated Erk1/2, JNK1/2, p38-MAPK and PI3K signalling peaking at 20min and induced cytoprotection against simulated ischemia-reperfusion injury which was blocked by the MEK1/2 inhibitor PD98059 but not the p38-MAPK inhibitor SB203580. In the absence of sIL-6R, IL-6 did not induce STAT1/3 phosphorylation, whereas IL-6/sIL-6R and LIF induced STAT1 and STAT3 phosphorylation. Furthermore, IL-6/sIL-6R induced phosphorylation of STAT1 Tyr(701) and STAT3 Tyr(705) were enhanced by SB203580. IL-6 and pheneylephrine (PE), but not LIF, induced cardiomyocyte iNOS expression and nitric oxide (NO) production. IL-6, LIF and PE induced cardiomyocyte hypertrophy, but with phenotypic differences in ANF and SERCA2 expression and myofilament organisation with IL-6 more resembling PE than LIF. Transfection of cardiomyocytes with full length or truncated chimaeric gp130 cytoplasmic domain/Erythropoietin receptor (EpoR) extracellular domain fusion constructs showed that the membrane proximal Box 1 and Box 2 containing region of gp130 was necessary and sufficient for MAPK and PI3K activation; hypertrophy; SERCA2 expression and iNOS/NO induction in the absence of JAK/STAT activation. In conclusion, IL-6 can signal in cardiomyocytes independent of sIL-6R and STAT1/3 and furthermore, that Erk1/2 and PI3K activation by IL-6 are both necessary and sufficient for induced cardioprotection. In addition, p38-MAPK may act as a negative feedback regulator of JAK/STAT activation in cardiomyocytes.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Survival / drug effects
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Cells, Cultured
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Cytokine Receptor gp130 / genetics
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Cytokine Receptor gp130 / metabolism*
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Flavonoids / pharmacology
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Humans
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Hypertrophy
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Imidazoles / pharmacology
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Interleukin-6 / genetics
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Interleukin-6 / metabolism*
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Interleukin-6 / pharmacology
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Janus Kinases / metabolism
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Leukemia Inhibitory Factor / genetics
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Leukemia Inhibitory Factor / metabolism
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Leukemia Inhibitory Factor / pharmacology
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Mice
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism*
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Nitric Oxide / metabolism
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Nitric Oxide Synthase Type II / metabolism
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation
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Pyridines / pharmacology
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Rats
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Receptors, Erythropoietin / genetics
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Receptors, Erythropoietin / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacology
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Reperfusion Injury / metabolism
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Reperfusion Injury / pathology
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STAT1 Transcription Factor / metabolism
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Flavonoids
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Imidazoles
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Interleukin-6
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Leukemia Inhibitory Factor
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Pyridines
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Receptors, Erythropoietin
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Recombinant Fusion Proteins
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Recombinant Proteins
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Cytokine Receptor gp130
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Nitric Oxide
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Nitric Oxide Synthase Type II
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Phosphatidylinositol 3-Kinases
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Janus Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one