Activation of AP-1 contributes to the beta-adrenoceptor-mediated myocardial induction of interleukin-6

作者：Rohrbach Susanne^*; Engelhardt Stefan; Lohse Martin J; Werdan Karl; Holtz Juergen; Muller Werdan Ursula

来源：Molecular Medicine, 2007, 13(11-12): 605-614.

DOI：10.2119/2007-00071.Rohrbach

The induction of proinflammatory cytokines in stressed myocardium is considered an innate immune response, but the role of p-adrenergic signaling in this proinflammatory response and the mechanisms of cardioprotection by beta-blockers are not fully understood. In the present study, we analyzed interleukin-6 (IL-6) formation and promoter activation in p-adrenoceptor-stimulated neonatal rat cardiomyocytes, in transgenic mice with cardiac overexpression of beta 1-adrenoceptors, and in failing human myocardium. IL-6 formation and release in cultured cardiomyocytes under beta-adrenoceptor stimulation requires the activation of activating protein-1 (AP-1) binding sites and of cAMP response elements (CRE) in the IL-6 promoter, but this release (140 +/- 6 pg/mL medium under 10(-6) M isoproterenol vs. 81 +/- 3 pg/mL unstimulated, P < 0.05) is moderate compared with that under inflammatory stimulation (855 +/- 44 pg/mL, enclotoxin 0.1 mu g/mL). Similarly, IL-6 is induced together with CRE- and AP-1 activation in the left ventricle (LV) of beta 1-transgenic mice before the onset of failure. However, we observed IL-6 induction with activation of NF-kappa B in addition to CRE and AP-1 in beta 1-transgenic mice at the age of 22 weeks and in explanted human LV after full development of failure. Treatment with beta-blockers lowered myocardial IL-6 as well as AP-1, NF-kappa B, and CRE activation. Therefore, the activation of AP-1 and CRE is part of P-adrenergic signal transduction for IL-6 induction in nonfailing and failing cardiomyocytes, whereas NF-kappa B activation contributes only in overloaded failing myocardium.

• 出版日期2007-12