title: Cytokine G-protein signaling crosstalk in cardiomyocytes: attenuation of Jak-STAT activation by endothelin-1.
abstract: The IL-6-related cytokines, LIF and cardiotrophin-1, are important growth promoting and cardioprotective agents for cardiomyocytes. However, factors that regulate their actions in the heart are poorly understood. In this study, we tested the hypothesis that endothelin-1, a peptide hormone that produces a pattern of cardiac hypertrophy distinct from LIF and cardiotrophin-1, modulates LIF-induced signaling in cardiomyocytes. Upon binding LIF or cardiotrophin-1, the LIF receptor alpha subunit (LIFRalpha) dimerizes with gp130, leading to activation of constitutively associated Jak1 proteins and LIFRalpha-gp130 tyrosine phosphorylation. We found that pretreatment of neonatal rat ventricular myocytes with endothelin-1 rapidly inhibited LIF-induced LIFRalpha tyrosine phosphorylation and Jak1 activation. This effect of endothelin-1 on LIFalpha and Jak1 was attenuated by the MEK1 inhibitor, PD98059, implicating involvement of the ERK kinases. Radioligand binding studies showed that inhibition of LIF signaling resulted from a reduction in cell surface LlFRalpha levels. Additionally, endothelin-1 was found to reduce LIF-induced STAT3 activation, as indexed by STAT3 Y705 phosphorylation. Finally, endothelin-1 and LIF were shown to induce opposite patterns of STAT3 activation in cardiomyocytes. LIF induced rapid, robust STAT3 Y705 phosphorylation; endothelin-1 produced a delayed, modest increase, and initially decreased STAT3 Y705 phosphorylation. Overall our findings indicate that endothelin-1 acts to temper IL-6-related cytokine signaling in cardiomyocytes, in particular STAT3 activation.
authors.affiliation: The Cardiovascular Research Institute, Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine, Temple, TX 76504, USA. gbooz@medicine.tamu.edu
authors.forename: George W
authors.initials: GW
authors.lastname: Booz
authors.forename: Jonathan N E
authors.initials: JN
authors.lastname: Day
authors.forename: Robert
authors.initials: R
authors.lastname: Speth
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Baker
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D053613:Janus Kinase 1; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000187:drug effects*; D018121:Receptors, Cytokine / Q000378:metabolism; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D019332:Endothelin-1; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507842:Lifr protein, rat; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507906:Jak1 protein, rat; D053613:Janus Kinase 1; D020928:Mitogen-Activated Protein Kinases; D020962:Heterotrimeric GTP-Binding Proteins