Urocortin induces interleukin-6 release from rat cardiomyocytes through p38 MAP kinase, ERK and NF-kappaB activation.
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 interleukin-6 (IL-6) release in a time- and dose-dependent fashion. Ucn stimulates activation of ERK and p38 MAP kinases, while both MEK1 and 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 alpha-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. The precise role of cardiac Ucn in vivo remains to be elucidated.
Huang
Man
M
Department of Pharmacology and Experimental Therapeutics Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, 27599-7178, USA.
Kempuraj
Duraisamy
D
Papadopoulou
Nikoletta
N
Kourelis
Taxiarchis
T
Donelan
Jill
J
Manola
Akrivi
A
Theoharides
Theoharis C
TC
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002469:Cell Separation; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D013997:Time Factors; D054832:Urocortins / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C101531:CRF receptor type 2; D015850:Interleukin-6; D016328:NF-kappa B; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases