(Hypertension. 1999;33:283-289.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Interleukin-1ß Regulation of the Human Brain Natriuretic Peptide Promoter Involves Ras-, Rac-, and p38 Kinase–Dependent Pathways in Cardiac Myocytes
From the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich.
Correspondence to Dr Margot C. LaPointe, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202-2689. E-mail mclapointe{at}aol.com
Abstract—Because both the brain natriuretic peptide (BNP) gene and the cytokine interleukin-1ß (IL-1ß) are induced in the infarcted myocardium, localized production of IL-1ß may regulate the BNP gene. We tested whether (1) IL-1ß regulates the human BNP promoter, (2) cis elements in the proximal promoter respond to IL-1ß, and (3) mitogen-activated protein kinase (MAPK) signaling pathways [p42/44, c-jun (JNK) and p38 kinase] are involved. We transferred the hBNP promoter coupled to a luciferase reporter gene or constructs with mutations in the proximal promoter GATA and M-CAT elements into neonatal rat ventricular myocytes and treated the cells with IL-1ß for 24 hours. IL-1ß–stimulated hBNP luciferase activity was eliminated by pretreatment with the transcription inhibitor actinomycin D. Both the p38 kinase inhibitor SB205380 (SB) and cotransfection of a dominant-negative mutant of p38 kinase reduced IL-1ß stimulation of the hBNP promoter. Dominant-negative mutants of Ras and Rac inhibited IL-1ß–stimulated hBNP luciferase activity by 64% and 90%, respectively. Constitutively active forms of Rac and MKK6, the immediate upstream activator of p38, were stimulatory; however, only the effect of MKK6 was inhibited by SB. Neither the p42/44 nor the JNK pathway was involved in the action of IL-1ß. Both IL-1ß and MKK6 activation of the hBNP promoter were partially reduced when the promoter contained a mutated M-CAT element. In summary, (1) IL-1ß is a transcriptional activator of the hBNP promoter; (2) IL-1ß acts through a Ras-dependent pathway not coupled to activation of p42/44 MAPK or JNK; (3) IL-1ß acts through a Rac-dependent pathway, but the downstream effector is not known; and (4) IL-1ß activation of p38 kinase is partially involved in regulation of the hBNP promoter, targeting the proximal M-CAT element.
Key Words: cell signaling • peptides, natriuretic • cytokines • M-CAT element
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