Regulation of the tumor necrosis factor-α promoter in the development of heart failure

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(1)Molecular mechanisms of the tumor necrosis factor-α (TNF-α) production by angiotensin II (ANGII)We examined the molecular mechanisms by which ANGII and lipopolysaccharide (LPS) up-regulate TNF-α gene expression. Competition analysis by electrophoretic mobility shift assay with and without specific antibodies showed that LPS increased binding of Sp1 and Sp3 to the Sp1 binding site, while Egr-1 was unimportant. With ANGII, binding of ATF-2/c-jun to the CRE site was required for TNF-α gene induction ; neither Ets nor NF-κB was essential.Mutation analysis confirmed that response to LPS relied upon the Sp1 site in the TNF-α promoter, while the CRE binding site was essential to stimulation by ANGII. We concluded that since TNF-α gene expression is transcriptionaly activated by ANGII or LPS via different cis-acting sequences in the TNF-α promoter and different transcriptional factors, mechanisms inducing TNF production differ between heart failure or cardiac hypertrophy and infectious disease.(2)Mechanisms of the TNF-α production in the human preripheral mononuclear cellsWe examined the production of TNF-α by endothelin-1 in the human peripheral mononuclear cells. Endothelin-1 significantly increased the TNF-α mRNA expression by the concentration-and time-dependent manner. Thus, the activation of mononuclear cells by endothelin-1 and/or ANGII may be important for the development of heart failure and/or cardiac hypertrophy.We believe that these minute study for the TNF-α production in heart failure or cardiac hypertrophy are necessary for the development of specific drugs.