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Cytokine G-protein signaling crosstalk in cardiomyocytes: Attentuation of Jak-STAT activation by endothelin-1

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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 α subunit (LIFRα) dimerizes with gp130, leading to activation of constitutively associated Jak1 proteins and LIFRα-gp130 tyrosine phosphorylation. We found that pretreatment of neonatal rat ventricular myocytes with endothelin-1 rapidly inhibited LIF-induced LIFRα tyrosine phosphorylation and Jak1 activation. This effect of endothelin-1 on LIFα 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 LIFRα 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.

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Authors and Affiliations

  1. The Cardiovascular Research Institute, Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine, Temple, TX, USA

    George W. Booz, Jonathan N.E. Day & Kenneth M. Baker

  2. Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, WA, USA

    Robert Speth

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  1. George W. Booz
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  2. Jonathan N.E. Day
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  3. Robert Speth
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  4. Kenneth M. Baker
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Booz, G.W., Day, J.N., Speth, R. et al. Cytokine G-protein signaling crosstalk in cardiomyocytes: Attentuation of Jak-STAT activation by endothelin-1. Mol Cell Biochem 240, 39–46 (2002). https://doi.org/10.1023/A:1020648425895

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