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This Article Accepted manuscript (PDF) All Versions of this Article: JME-08-0120v1 42/5/397    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Huang, M. Articles by Theoharides, T. Search for Related Content PubMed PubMed Citation Articles by Huang, M. Articles by Theoharides, T.

M Huang, Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, United States
D Kempuraj, Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, United States
N Papadopoulou, Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, United States
T Kourelis, Boston, United States
J Donelan, Boston, United States
A Manola, Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, United States
T Theoharides, Pharmacology and Experimental Therapeutics, Tufts University, Boston, United States

Correspondence: Theoharis Theoharides, Email: theoharis.theoharides{at}tufts.edu

Abstract

Corticotropin-releasing hormone (CRH) and its structurally related peptide urocortin (Ucn) are released under stress. Ucn is a potent agonist for CRH-receptor 2 (CRH-R2), which is strongly expressed in rodent heart. Stress induces Ucn mRNA expression in the heart where it may be cardioprotective. However, increasing evidence indicates that Ucn may also have pro-inflammatory actions. Here we show that neonatal rat cardiomyocytes express CRH-R2 by Western blot analysis and Ucn induces IL-6 release in a time- and dose-dependent fashion. Ucn stimulates activation of ERK and p38 MAP kinases, while both a MEK1 and a p38 inhibitor block Ucn-induced IL-6 release. Ucn also activates nuclear factor kappa B (NF-kappaB) and a NF-kappaB inhibitor blocks Ucn-induced IL-6 release. Finally, the CRH-R antagonists -helical (9-41) CRH and Astressin-2B completely inhibit Ucn-induced IL-6 release, as well as activation of ERK, p38 and NF-kappaB. These findings indicate that Ucn induces IL-6 synthesis and release from neonatal rat cardiomyocytes. Our findings suggest that even though Ucn may confirm some protection on cardiomyocyte survival, it can also release IL-6, which is an independent risk factor for acute coronary syndrome (ACS). The precise role of cardiac Ucn in vivo remains to be elucidated.