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European Journal of Heart Failure 2004 6(7):869-875; doi:10.1016/j.ejheart.2004.02.007
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© 2004 European Society of Cardiology

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

Mamoru Satoh*, Junji Iwasaka, Motoyuki Nakamura, Tomonari Akatsu, Yudai Shimoda and Katsuhiko Hiramori

Second Department of Internal Medicine, Iwate Medical University School of Medicine Uchimaru 19-1, Morioka 020-8505, Iwate, Japan

* Corresponding author. Tel.: +81-19-651-5111; Fax: +81-19-651-0401 E-mail address: m_satoh{at}imu.ncvc.go.jp


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
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.

Aims: 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).

Methods and 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).

Conclusion: 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.

Key Words: Flow cytometry • Metalloproteinase • mRNA • Real-time PCR

Received June 27, 2003; Revised December 19, 2003; Accepted February 23, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Tumor necrosis factor-{alpha} (TNF-{alpha}) converting enzyme (TACE) has recently been recognized as one of the metalloproteinase (MMP)-disintegrins that release soluble TNF-{alpha} [1]. TNF-{alpha} is well known as one of the proinflammatory cytokines with negative inotropic activity. TACE acts by cleaving within the extracellular domain of membrane-bound pro-TNF-{alpha} [1,2]. It has been suggested that TACE is expressed ubiquitously and that several types of TACE knock-out cells lose TNF-{alpha} processing activity, indicating that TACE is responsible for pro-TNF-{alpha} shedding in various cell types such as peripheral blood mononuclear cells (PBMC), neutrophils and endothelial cells [3]. Our previous studies have shown a direct relationship between mRNA expression of both TNF-{alpha} and TACE in human myocardial tissue and circulating leukocytes [4,5]. Recent studies indicate that a newly developed TACE inhibitor may be useful for treatment of diseases such as arthritis and endotoxemia, in which excessive production of TNF-{alpha} is thought to play a central role [6,7].

Since elevated plasma levels of TNF-{alpha} have been reported in patients with congestive heart failure (CHF) [8], TNF-{alpha} may potentially be involved in the maladaptive compensation seen in CHF. The high levels of circulating TNF-{alpha} are also known to contribute to the progression of CHF [9]. However, plasma levels of TNF-{alpha} are only transiently elevated, suggesting that single blood sampling may not actually reflect the immune response of these inflammatory mediators [10]. Anker et al. have firstly hypothesized that activated PBMC plays an important role in the pathophysiology of immune activation in patients with CHF [11]. Nozaki et al. have also suggested that activated PBMC may be an important cellular source of these increased levels of proinflammatory cytokines, and may modulate the process of shedding of soluble TNF-{alpha} in CHF [12]. In view of these findings, PBMC-mediated immune response may be involved in the development and progression of CHF. However, it has been uncertain whether TACE regulates the maturation of TNF-{alpha} in PBMC in human CHF.

This study has analyzed TACE and TNF-{alpha} mRNAs, and intracellular TACE and TNF-{alpha} in protein-positive cells in PBMC obtained from CHF patients and healthy subjects in order to determine whether there is underlying activation of the TACE–TNF-{alpha} system in this disorder.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Subjects
Peripheral blood samples were obtained from 46 patients with CHF. The CHF group included 39 males and seven females (mean age 64±3 years). The origin of heart failure was ischemic heart disease in 15, non-ischemic cardiomyopathy in 17 (dilated cardiomyopathy, hypertensive heart disease, arrhythmogenic right ventricular cardiomyopathy with left ventricular [LV] dysfunction, dilated phase of hypertrophic cardiomyopathy), valvular heart disease in 13, and congenital heart disease in one. CHF patients with valvular heart disease were consisted of end-staged valvular heart diseases with LV dysfunction, and those patients did not undergo surgery at the time of this study. The diagnosis of CHF was based on a history of CHF at least 6 months with symptoms, symptomatic exercise intolerance, and reduced LV function as assessed by echocardiography. Patients were excluded from study if they had clinical signs of acute infection, severe renal failure, rheumatoid disease, or myocardial infarction within the previous 6 months or if they were suspected of having a malignant or a primary wasting disorder. The CHF group was divided into mild (n=19) and severe (n=27) subgroups according to NYHA functional class (I or II, and III or IV, respectively). The clinical variables of the CHF population were given in Table 1. Blood samples were also obtained from 22 healthy subjects as controls (males:females 14:8, mean age 58±4 years). The study protocol was approved by our hospital ethics committee, and informed consent was obtained from all subjects.


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  		Table 1 The clinical variables of CHF population

 
2.2. Cell preparation and culture conditions
PBMC were isolated from heparinized peripheral blood samples obtained from CHF patients and controls by Ficoll–Paque density gradient centrifugation and lymphocyte separation solution (Nacalai tesque, Inc). Cells were resuspended in either non-activating medium (10% heat-inactivated FCS [GIBCO BRL]-supplemented RPMI 1640 [Sigma] with 40 µg/ml Brefeldin A [Sigma]) or activating medium (10% heat-inactivated FCS [GIBCO BRL]-supplemented RPMI 1640 with 40 ng/ml phorbol 12-myristate 13-acetate [Calbiochem] and 4 µg/ml ionomycin [Sigma]) and then incubated for 4 h at 37 °C in 5% CO2. FCS was free of pyrogens or endotoxins. To assess for viability of PBMC, we have performed trypan blue exclusion staining of cultured PBMC (GIBCO BRL).

2.3. Extraction of total RNA
Total RNA was extracted from PBMC by the acid guanidinium thiocyanate–phenol–chloroform method and treated with RNase I (GIBCO BRL) [13].

2.4. Oligonucleotides of primers and probes
Published cDNA sequences for human TACE and TNF-{alpha} were used for primer and probe construction [1,14]. The following primers and probes were used for relative quantification of targeted gene expression: for TACE: forward primer 5'-ACC TGA AGA GCT TGT TCA TCG AG-3', reverse primer 5'-CCA TGA AGT GTT CCG ATA GAT GTC-3', and TaqMan probe 5'-TTG GTG GTA GCA GAT CAT CGC TTC T-3'; for TNF-{alpha}: forward primer 5'-CTT CTC CTT CCT GAT CGT GG-3', reverse primer 5'-GCT GGT TAT CTC TCA GCT CCA-3', and TaqMan probe 5'-CAG GCA GTC AGA TCA TCT TCT CGA AC-3'. For all samples, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was amplified using TaqMan GAPDH control reagents as an internal control (PE Biosystem, Foster City, CA, USA).

2.5. Real-time RT-PCR
We analyzed TACE and TNF-{alpha} mRNA expression levels using a quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) method as previously described [4,5]. The cDNA was synthesized and amplified from 100 ng of total RNA and tenfold serial dilutions of human control RNA (PE Biosystem) by reverse transcription and PCR using Taq Man EZ RT-PCR kit (PE Biosystem). The cDNA products were synthesized at 60 °C for 30 min and amplified with 40 cycles of PCR, with each cycle consisting of denaturation at 94 °C for 20 s, and annealing and extension at 62 °C for 1 min. A quantitative PCR method was developed using detection and 5' nuclease assay by an ABI PRISM 7700 sequence detector (PE Biosystem).

2.6. Flow cytometric analysis
Flow cytometric analysis was carried out with a FACScan flow cytometer and CellQuest software (Becton Dickinson, Mountain View, CA, USA). PBMC were washed and permeabilized with FACS Permeabilizing Solution (Becton Dickinson) for 10 min. Intracellular TNF-{alpha} and TACE were then stained with FITC-conjugated mouse anti-human TNF-{alpha} antibody (Becton Dickinson) or Alexa488 (Molecular Probes)-conjugated goat anti-human TACE antibody (Sant Cruz) for 30 min. Isotype-matched irrelevant control IgG conjugated with FITC were used as controls (PharMingen). The PBMC population was selected on the basis of cell size (FSC) and granularity (SCC) (Fig. 1a,b). Histograms were then generated using PBMC region, which allowed measurement of intracellular TACE and TNF-{alpha} levels using median fluorescence intensity (MFI) (Fig. 1c,d).


Figure 1
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  		Fig. 1 Dot plots and histograms representing intracellular TACE and TNF-{alpha} levels in PBMC. The PBMC population (R1) can be gated in the dot plot using cell size (FSC) vs. cell granularity (SSC) (a and b). Using the histograms, intracellular fluorescence can be measured. The ordinate relates to the relevant cell number, while fluorescence intensity can be seen on the abscissa, representing intracellular TACE (c) and TNF-{alpha} (d) levels. Shaded and clear histograms show activated and non-activated PBMC, respectively. A shift to the right demonstrates an increase in the amount of TACE and TNF-{alpha} levels in a cell. A peak can be observed for PBMC. Specific intracellular fluorescence levels can be quantified from these histograms for each case.

 
2.7. Measurement of culture supernatant TNF-{alpha} levels
TNF-{alpha} levels in culture supernatant were determined by slide phase enzyme amplified sensitivity immunoassay kit (BIOSOURCE TNF-{alpha} EASIA kit, BioSource Europe S.A., Nivelles, Belgium). The color generated was determined by measuring the OD at 490 nm in a spectrophotometric microtiter plate reader (Labsystem Multiskan, BICHROMATIC; Labsystem). The expected level in normal plasma was 6 pg/ml. The minimum detectable concentration was estimated to be 3 pg/ml. The inter- and intra-assay coefficients of variation of EASIA kit were 8.0% and 3.7%, respectively.

2.8. Statistical analysis
All values are presented as mean±S.E. Culture supernatant TNF-alpha levels were log-normally distribution, and comparisons were made between sets of log-transformed data. Statistically, the differences in TNF-{alpha} and TACE expression levels between CHF patients and controls were analyzed by ANOVA. Pearson's correlation coefficients were used to examine the relationship between mRNA expression levels and clinical parameters. A value of P<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. TACE and TNF-{alpha} mRNA levels in PBMC
After in vitro activation, expression levels of TACE and TNF-{alpha} mRNAs in PBMC were significantly higher in CHF patients than in controls (TACE mRNA/GAPDH ratio: 2.06±0.23 vs. 0.38±0.09, P<0.001; TNF-{alpha} mRNA/GAPDH ratio: 1.64±0.21 vs. 0.46±0.06, P<0.001). There was a positive correlation between TACE and TNF-{alpha} mRNA levels in CHF patients (r=0.60, P<0.001) (Fig. 2). 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} mRNAs in PBMC were significantly higher in severe CHF patients (NYHA III or IV) than in mild CHF patients (NYHA I or II) (TACE mRNA/GAPDH ratio: 2.69±0.32 vs. 1.17±0.15, P<0.001; TNF-{alpha} mRNA/GAPDH ratio: 2.29±0.29 vs. 0.72±0.09, P<0.001) (Fig. 3).


Figure 2
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  		Fig. 2 Correlation plot between TACE and TNF-{alpha} mRNA levels in activated PBMC obtained from CHF patients.

 


Figure 3
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  		Fig. 3 TACE and TNF-{alpha} mRNA levels in PBMC from controls and from mild and severe CHF subgroups. (a) TACE mRNA levels in two CHF subgroups and controls. (b) TNF-{alpha} mRNA levels in two CHF subgroups and controls. Each bar and error bar indicates mean±S.E.

 
3.2. Intracellular TACE and TNF-{alpha} levels in PBMC
Intracellular TACE and TNF-{alpha} MFI levels in activated PBMC were higher in CHF patients than in controls (TACE MFI levels: 5.2±0.4 vs. 1.5±0.1, P<0.001; TNF-{alpha} MFI levels: 5.1±0.4 vs. 1.4±0.1, P<0.001). There was a positive correlation between intracellular TACE and TNF-{alpha} MFI levels within PBMC in CHF patients (r=0.76, P<0.001) (Fig. 4). These levels were higher in the severe CHF subgroup than the mild CHF group (TACE MFI levels: 6.7±0.3 vs. 3.1±0.4, P<0.001; TNF-{alpha} MFI levels: 6.3±0.4 vs. 3.4±0.3, P<0.001) (Fig. 5). Intracellular TACE and TNF-{alpha} MFI levels were also positively correlated with the respective mRNA levels (TACE levels: r=0.80, P<0.001; TNF-{alpha} levels: r=0.67, P<0.001).


Figure 4
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  		Fig. 4 Correlation plot between TACE and TNF-{alpha} MFI levels in activated PBMC obtained from CHF patients.

 


Figure 5
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  		Fig. 5 Intracellular TACE and TNF-{alpha} MFI levels in activated PBMC obtained from controls and two CHF subgroups. (a) Intracellular TACE MFI levels in two CHF subgroups and controls. (b) Intracellular TNF-{alpha} MFI levels in two CHF subgroups and controls. Each bar and error bar indicates mean±S.E.

 
3.3. TNF-{alpha} levels in culture supernatant
TNF-{alpha} levels in culture supernatant were higher in CHF patients than in controls (8.88±1.0 vs. 3.0±0.4 ng/ml, P=0.001). Levels were also higher in severe CHF patients than in mild CHF patients (10.8±1.4 vs. 6.1±1.5 ng/ml, P=0.03).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
4.1. Inflammatory response in CHF
Although several studies have demonstrated that circulating TNF-{alpha} levels are elevated in patients with severe CHF [8,9], it is noted that plasma levels of TNF-{alpha} in patients with CHF vary markedly. In a study of patients with severe CHF followed up over a 1 year period, plasma TNF-{alpha} levels were not detectable on at least one occasion for each patient [15], suggesting that plasma levels of TNF-{alpha} may not reflect host production of TNF-{alpha}. In addition, the shedding process of the soluble form of this protein in CHF has not been ascertained. This study showed high levels of TACE and TNF-{alpha} in PBMC obtained from subjects with CHF using an ex vivo activated model of local TNF-{alpha} production. There was a positive correlation between TACE and TNF-{alpha} levels in activated PBMC in CHF. These results indicate that PBMC may represent a significant source of TNF-{alpha} maturation in CHF. In a human monocytic cell line model, the expression of recombinant TACE tightly controlled the process that converts precursor TNF-{alpha} to the mature form [2]. These findings suggest that expression of TACE activates not only TNF-{alpha} mRNA transcription, but also the maturation of TNF-{alpha} protein in PBMC from patients with CHF. In a human whole blood model, LPS-stimulated production of TNF-{alpha} tended to be higher in patients with heart failure than in healthy volunteers [16]. It has also been reported that altered activation of PBMC contributes to the pathogenesis of heart failure [17]. Other studies have suggested that PBMC may modulate the responsiveness of the TNF-{alpha} shedding process via TNF receptor II in CHF [10,18]. In animal studies using chimeric mice that are null for TACE activity, T-cells derived from these mice express a form of TACE that lacks a portion of the catalytic domain and is unable to process proTNF-{alpha} [1,2]. These reports and the present results suggest that the activation of TACE in PBMC may be responsible for the release of TNF-{alpha} by proteolytic cleavage of the membrane-associated precursor form in CHF.

4.2. Clinical severity and activated TACE–TNF-{alpha} system in CHF
Several reports have demonstrated that TNF-{alpha}-producing PBMC may be a potential biochemical mediator of the progression of CHF and left ventricular dysfunction [10,16], and that cellular and humoral immune disturbances through PBMC activation may play a role in the pathogenesis and progression of CHF [17,18]. Several studies have reported that abnormalities in the cytokine network were pronounced in patients with the most severe heart failure [17,19]. These reports have suggested that the abnormalities of immune response were related to the severity of CHF. The experimental models with failing heart have suggested that activated PMBC, such as cytotoxic T lymphocytes, may have a role in inducing and augmenting myocardial damage by lysing autoantigen-expressing cells and secreting cytotoxic cytokines [20,21]. However, the mechanism behind the elevated secretion of TNF-{alpha} by PBMC in CHF remains unknown. In an animal model, chronic infusion of TNF-{alpha} induced ventricular dysfunction and dilatation without inflammatory infiltrate and myocyte necrosis [22]. This model suggests that TNF-{alpha} could directly induce a negative inotropic effect and ventricular remodeling in the heart [22]. Anker et al. and Niebauer et al. have reported that CHF patients exhibit immune activation, which may be induced by bacterial translocation from the intestine to the blood stream due to venous congestion and altered gut permeability [11,23]. This activation of the immune system may account for the elevation of TNF-{alpha} secretion by PMBC. Although the present study was unable to confirm whether increased TACE levels directly cause TNF-{alpha} production to increase in PBMC in CHF, there was a positive correlation between TACE and TNF-{alpha} levels in activated PBMC obtained from patients with CHF. The present study also found a significant correlation between levels of TACE and TNF-{alpha} and clinical severity of heart failure. Several experimental studies have reported that inflammatory conditions, such as endotoxin challenge and bacterial LPS stimulation of cultured PBMC, mediated to TACE like metalloproteinase overexpression, and the metalloproteinase stimulated TNF-{alpha} shedding process [24,25]. From these observations, it may be hypothesized that activation of TACE synthesis in PBMC may play an important mediating role in the maturation of TNF-{alpha} in human CHF. TACE produced by PBMC may contribute to alterations in systemic metabolism and TNF-{alpha} maturation in these patients, leading to the progression of heart failure. In addition, a rat model of arthritis has recently shown that a dual inhibitor of TACE and MMPs inhibited an increase in levels of TNF-{alpha} secretion [6]. Dekkers et al. have reported that orally administered MMP inhibitor markedly reduced circulating levels of soluble TNF-{alpha} after LPS injection in healthy humans [7]. Recently, ATTACH-trial that used mechanisms to neutralize the mature form of TNF-{alpha} has resulted in worsening heart failure [26]. However, the inhibition of transcriptional and translational activation of TNF-{alpha} has been of benefit to patients with CHF [27,28]. TACE may therefore represent a significant target enzyme for the design of specific synthetic inhibitors as a novel therapeutic agent in CHF.

In conclusion, these findings indicate that TACE may regulate translational and post-translational processing of TNF-{alpha} in PBMC in CHF. This implies that TACE is an important regulator of TNF-{alpha} maturation in PBMC, making it a potential target for inhibition of a cellular source of TNF-{alpha} in CHF.


   Acknowledgements
 
This work was supported by a Grant-in-Aid for General Scientific Research from the Japanese Ministry of Education, Science, Sports and Culture (No. 12770348).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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