Beta-adrenergic stimulation induces interleukin-18 expression via beta2-AR, PI3K, Akt, IKK, and NF-kappaB.
We investigated whether beta-adrenergic receptor (beta-AR) stimulation induces the expression of interleukin (IL)-18, a proinflammatory cytokine, in myocardium and in cardiac-derived endothelial cells (CDEC) via activation of nuclear factor (NF)-kappaB. Our results indicate that isoproterenol (ISO) activates NF-kappaB DNA binding activity, and induces myocardial and systemic elaboration of IL-18 via beta2-AR signaling. Furthermore, in CDEC, ISO increased basal and inducible promoter activities, increased IL-18 gene transcription and mRNA stability, and induced IL-18 expression via beta2-AR agonism. Signaling required GiPI3K, PI3K, Akt, IKK, and NF-kappaB. In conclusion, our results indicate for the first time that isoproterenol induces myocardial and systemic elaboration of IL-18 via a beta2-AR and NF-kappaB-dependent mechanism. Similar events may occur in heart failure, a disease state characterized by sustained beta-AR activation.
Chandrasekar
Bysani
B
Division of Cardiology, The University of Texas Health Science Center, San Antonio, TX, USA. Chandraseka@uthscsa.edu
Marelli-Berg
Federica M
FM
Tone
Masahide
M
Bysani
Sailaja
S
Prabhu
Sumanth D
SD
Murray
David R
DR
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D051550:I-kappa B Kinase; D020382:Interleukin-18 / Q000235:genetics*; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D051550:I-kappa B Kinase; D020382:Interleukin-18; D007545:Isoproterenol; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018343:Receptors, Adrenergic, beta-2; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse