A role for the extracellular signal-regulated kinase and p38 mitogen-activated protein kinases in interleukin-1 beta-stimulated delayed signal tranducer and activator of transcription 3 activation, atrial natriuretic factor expression, and cardiac myocyte morphology.
We have demonstrated that two hypertrophic agents, interleukin-1 beta (IL-1 beta) and leukemic inhibitory factor (LIF), altered cardiac myocyte morphology with striking similarity and prompted us to investigate the common actions of these cytokines. We compared the phosphorylation/activation of signal tranducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK), p38(MAPK), and c-Jun N-terminal kinase mitogen-activated protein kinases (MAPKs). The phosphorylation of STAT3 by IL-1 beta was delayed (>60 min), whereas the response to LIF was rapid (<10 min) and transient. We confirmed that IL-1 beta potently stimulated all three MAPK subfamilies. In contrast, LIF promoted strong activation of ERKs, marginal activation of p38(MAPK), and no c-Jun N-terminal kinase activation. To test the roles of ERKs and p38(MAPK), myocytes were pretreated with PD98059 and SB203580. Either inhibitor alone prevented STAT3 phosphorylation, implicating ERKs and p38(MAPK) in the delayed STAT3 response to IL-1 beta. The interplay of MAPKs and STAT3 phosphorylation in regulating IL-1 beta-stimulated hypertrophy was investigated by evaluating the effect of MAPK inhibitors on atrial natriuretic factor (ANF) expression and myocyte morphology. The specific inhibition of either ERK or p38(MAPK) attenuated the IL-1 beta- or LIF-stimulated ANF expression by up to 70%. Inhibition was not further increased in the presence of both inhibitors. Furthermore, although individual inhibition of ERK or p38(MAPK) did not affect morphology, co-treatment with both inhibitors abrogated the hypertrophic morphology stimulated by IL-1 beta but not by LIF. Taken together, our data indicate that the activation of ERK and p38(MAPK) is essential in regulating a delayed STAT3 phosphorylation as well as changes in ANF expression and morphology that follow IL-1 beta treatment. Thus, the role of MAPKs in the hypertrophic response can be dictated at least partly by the nature of the hypertrophic agent employed.
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Department of Biochemistry, University of Western Australia, Crawley 6009, Australia.
Long
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Bogoyevitch
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D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000235:genetics*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles; D006984:Hypertrophy; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D021381:Protein Transport; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D000209:Acute-Phase Proteins; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006131:Growth Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D003513:Cycloheximide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one