Increased expression of tumor necrosis factor‐α converting enzyme and tumor necrosis factor‐α in peripheral blood mononuclear cells in patients with advanced congestive heart failure

Abstract

Tumor necrosis factor-alpha converting enzyme (TACE) has recently been identified as a metalloproteinase-disintegrin, which converts pro-tumor necrosis factor-alpha (TNF-alpha) to the mature form, and is an important mediator in the pathogenesis of CHF. In order to establish the importance of TACE in the regulation of TNF-alpha synthesis in peripheral blood mononuclear cells (PBMC), we analyzed mRNAs and protein-positive cells of both TACE and TNF-alpha in PBMC obtained from patients with congestive heart failure (CHF). PBMC were obtained from 46 patients with CHF and 22 controls. PBMC were activated by phorbol 12-myristate 13-acetate and ionomycin and assessed for TACE and TNF-alpha mRNAs by real-time RT-PCR, intracellular TACE and TNF-alpha levels by flow cytometry, and TNF-alpha secretion by supernatant ELISA. Levels of TACE and TNF-alpha mRNAs, intracellular TACE and TNF-alpha, and supernatant TNF-alpha were higher in CHF than in controls (P<0.001). There was a positive correlation between TACE and TNF-alpha levels in CHF patients (mRNA: r=0.60, P<0.001, intracellular protein levels: r=0.76, P<0.001). When the CHF group was divided into two subgroups by NYHA functional class (I and II vs. III and IV), levels of TACE and TNF-alpha were significantly higher in severe CHF patients (NYHA III or IV) than in mild CHF patients (NYHA I or II) (mRNA: P<0.001; intracellular protein levels: P<0.001). These results demonstrate that in patients with CHF, and especially those with severe CHF, TACE expression in PBMC increases with TNF-alpha expression. These observations suggest that TACE in PBMC is an important regulator of TNF-alpha maturation, meaning that TACE may be a potential target for the inhibition of cellular TNF-alpha production in CHF.