Activation of AP-1 contributes to the beta-adrenoceptor-mediated myocardial induction of interleukin-6.
The induction of proinflammatory cytokines in stressed myocardium is considered an innate immune response, but the role of beta-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 beta-adrenoceptor-stimulated neonatal rat cardiomyocytes, in transgenic mice with cardiac overexpression of beta1-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, endotoxin 0.1microg/mL). Similarly, IL-6 is induced together with CRE- and AP-1 activation in the left ventricle (LV) of beta1-transgenic mice before the onset of failure. However, we observed IL-6 induction with activation of NF-kappaB in addition to CRE and AP-1 in beta1-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-kappaB, and CRE activation. Therefore, the activation of AP-1 and CRE is part of beta-adrenergic signal transduction for IL-6 induction in nonfailing and failing cardiomyocytes, whereas NF-kappaB activation contributes only in overloaded failing myocardium.
Rohrbach
Susanne
S
Institute of Pathophysiology, Martin Luther University Halle-Wittenberg, Germany. susanne.rohrbach@medizin.uni-halle.de
Engelhardt
Stefan
S
Lohse
Martin J
MJ
Werdan
Karl
K
Holtz
Juergen
J
Muller-Werdan
Ursula
U
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D006333:Heart Failure / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D017931:DNA Primers; D015850:Interleukin-6; D011943:Receptors, Adrenergic, beta; D018808:Transcription Factor AP-1