Abstract
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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adrenergic beta-Agonists / pharmacology*
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Animals
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Cells, Cultured
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / physiology
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I-kappa B Kinase
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Interleukin-18 / genetics*
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Isoproterenol / pharmacology*
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Male
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Mice
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Mice, Inbred C57BL
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Myocardium / cytology
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Myocardium / enzymology
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Myocardium / metabolism*
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NF-kappa B / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism*
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Promoter Regions, Genetic
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Receptors, Adrenergic, beta-2 / metabolism*
Substances
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Adrenergic beta-Agonists
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Interleukin-18
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NF-kappa B
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Proto-Oncogene Proteins
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Receptors, Adrenergic, beta-2
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Chuk protein, mouse
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I-kappa B Kinase
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Ikbkb protein, mouse
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Ikbke protein, mouse
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Isoproterenol