title: Interleukin-1beta regulates the human brain natriuretic peptide promoter via Ca(2+)-dependent protein kinase pathways.
abstract: We have shown that interleukin-1beta (IL-1beta) activates the human brain natriuretic peptide (hBNP) promoter via a transcriptional mechanism. Others have reported that changes in intracellular calcium (Ca(2+)) mediate the action of IL-1beta. We questioned whether Ca(2+) and Ca(2+)-dependent pathways mediate IL-1beta regulation of the hBNP promoter in cardiac myocytes. The hBNP promoter (-1818 to +100) coupled to a luciferase cDNA reporter gene was transferred into neonatal cardiac myocytes. Cells were then treated with agents that modify Ca(2+) levels or inhibit Ca(2+)-dependent kinases, and luciferase activity was measured as an index of hBNP promoter activity. The Ca(2+) ionophore A23187 increased hBNP promoter activity; however, neither EGTA nor nifedipine reduced IL-1beta-stimulated promoter activity. Long-term treatment with thapsigargin, which depletes intracellular Ca(2+) stores, decreased basal promoter activity and blocked the effect of IL-1beta. Inhibition of protein kinase C completely blocked IL-1beta-stimulated hBNP promoter activity, whereas inhibition of Ca(2+)/calmodulin-dependent kinase II decreased promoter activity by 40%. In contrast, inhibition of the Ca(2+)-regulated phosphatase calcineurin by cyclosporin A had no effect. These data suggest that (1) Ca(2+) activates the hBNP promoter; (2) release of Ca(2+) from intracellular stores is important to IL-1beta regulation of the hBNP promoter, but transport via voltage-sensitive Ca(2+) channels is not; (3) protein kinase C and Ca(2+)/calmodulin-dependent kinase II mediate the action of IL-1beta; and (4) the phosphatase calcineurin is not involved in IL-1beta regulation of the hBNP promoter. Thus, Ca(2+) and Ca(2+)-dependent pathways are critical to IL-1beta regulation of the hBNP promoter.
authors.affiliation: Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI 48202-2689, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: He
authors.forename: M C
authors.initials: MC
authors.lastname: LaPointe
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D006332:Cardiomegaly / Q000201:enzymology; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D020097:Natriuretic Peptide, Brain / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
chemical_list: D007375:Interleukin-1; D020097:Natriuretic Peptide, Brain; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019703:Calcineurin; D002118:Calcium