Interleukin-1β regulation of the human brain natriuretic peptide promoter involves Ras-, Rac-, and p38 kinase-dependent pathways in cardiac myocytes

被引:76
作者
He, Q [1 ]
LaPointe, MC [1 ]
机构
[1] Henry Ford Hosp, Hypertens & Vasc Res Div, Detroit, MI 48202 USA
关键词
cell signaling; peptides; natriuretic; cytokines; M-CAT element;
D O I
10.1161/01.HYP.33.1.283
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
Because both the brain natriuretic peptide (BNP) gene and the cytokine interleukin-1 beta (IL-1 beta) are induced in the infarcted myocardium, localized production of IL-1 beta may regulate the BNP gene. We tested whether (1) IL-1 beta regulates the human BNP promoter, (2) cis elements in the proximal promoter respond to IL-1 beta, 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-1 beta for 24 hours. IL-1 beta-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-1 beta stimulation of the hBNP promoter. Dominant-negative mutants of Ras and Rac inhibited IL-1 beta-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 SE. Neither the p42/44 nor the JNK pathway was involved in the action of IL-1 beta. Both IL-1 beta and MKK6 activation of the hBNP promoter were partially reduced when the promoter contained a mutated M-CAT element. In summary, (1) IL-1 beta is a transcriptional activator of the hBNP promoter; (2) IL-1 beta acts through a Ras-dependent pathway not coupled to activation of p42/44 MAPK or JNK; (3) IL-1 beta acts through a Rac-dependent pathway, but the downstream effector is not known; and (4) IL-1 beta activation of p38 kinase is partially involved in regulation of the hBNP promoter, targeting the proximal M-CAT element.
引用
收藏
页码:283 / 289
页数:7
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