Interleukin-1β Regulation of the Human Brain Natriuretic Peptide Promoter Involves Ras-, Rac-, and p38 Kinase–Dependent Pathways in Cardiac Myocytes

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Abstract
—Because both the brain natriuretic peptide (BNP) gene and the cytokine interleukin-1β (IL-1β) are induced in the infarcted myocardium, localized production of IL-1β may regulate the BNP gene. We tested whether (1) IL-1β regulates the human BNP promoter, (2)ciselements in the proximal promoter respond to IL-1β, 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-1β for 24 hours. IL-1β–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-1β stimulation of the hBNP promoter. Dominant-negative mutants of Ras and Rac inhibited IL-1β–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-1β. Both IL-1β and MKK6 activation of the hBNP promoter were partially reduced when the promoter contained a mutated M-CAT element. In summary, (1) IL-1β is a transcriptional activator of the hBNP promoter; (2) IL-1β acts through a Ras-dependent pathway not coupled to activation of p42/44 MAPK or JNK; (3) IL-1β acts through a Rac-dependent pathway, but the downstream effector is not known; and (4) IL-1β activation of p38 kinase is partially involved in regulation of the hBNP promoter, targeting the proximal M-CAT element.

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