Increased expression of tumor necrosis factor-alpha converting enzyme and tumor necrosis factor-alpha in peripheral blood mononuclear cells in patients with advanced congestive heart failure.
BACKGROUND
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.


OBJECTIVE
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).


RESULTS
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).


CONCLUSIONS
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.
Satoh
Mamoru
M
Second Department of Internal Medicine, Iwate Medical University School of Medicine, Uchimaru 19-1, Morioka 020-8505, Iwate, Japan. m_satoh@imu.ncvc.go.jp
Iwasaka
Junji
J
Nakamura
Motoyuki
M
Akatsu
Tomonari
T
Shimoda
Yudai
Y
Hiramori
Katsuhiko
K
D051722:ADAM Proteins / Q000096:biosynthesis*; D000072198:ADAM17 Protein; D000368:Aged; D015415:Biomarkers / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006333:Heart Failure / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation
D015415:Biomarkers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human