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European Journal of Heart Failure 2003 5(4):435-442; doi:10.1016/S1388-9842(03)00002-3
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© 2003 European Society of Cardiology

Pulmonary endothelium as a site of synthesis and storage of interleukin-6 in experimental congestive heart failure

Roger Gaertnera, Delphine Lepailleur-Enoufa, Walter Gonzaleza, Antonino Nicolettib, Chantal Mandetb, Monique Philippea, Jean-Jacques Mercadiera and Jean-Baptiste Michela,*

a INSERM U460, Cardiovascular Remodelling, CHU Xavier-Bichat 16 rue Henri Huchard, 75018 Paris, France
b U430, Hôpital Broussais Paris, France

* Corresponding author. Tel.: +33-1-44-85-61-60; fax: +33-1-44-85-61-57 E-mail address: u460{at}bichat.inserm.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Pulmonary endothelium is an early upstream hemodynamic target of left ventricular dysfunction. Interleukin 6 (IL-6) is a pro-inflammatory cytokine reported to increase in congestive heart failure (CHF) patients.

Aims: We sought to determine the origin of IL-6, IL-6 receptor (IL-6R) and gp130 in experimental CHF.

Methods: We used rats with coronary artery ligation as an experimental model of either compensated or decompensated heart failure. Lung and aorta samples were analysed by RT-PCR, ELISA and immunohistochemistry for IL-6 and its receptors.

Results: IL-6 mRNA expression increased in the lung of rats with decompensated heart failure and was positively correlated with infarct severity whereas IL-6R mRNA decreased in the lung of myocardial infarction rats and gp130 mRNA remained unchanged. In contrast, there were no changes in IL-6 mRNA expression in the aorta and left ventricular myocardium. IL-6 peptide content as determined by ELISA and Western Blot in lung tissue was 2-fold higher in decompensated heart failure as compared to control rats. These data were confirmed by immunohistochemistry showing a preferential endothelial localization of IL-6 in the CHF lung. IL-6 peptide was also present in the pleural effusion of decompensated heart failure and was positively correlated with IL-6 mRNA expression in the lungs of decompensated HF rats. Pulmonary IL-6 overexpression was associated with nuclear translocation of NF-{kappa}B and cytosolic degradation of I{kappa}B.

Conclusion: Dysfunctional pulmonary endothelium is a source of synthesis and storage of IL-6 in an experimental model of CHF.

Key Words: Myocardial infarction • Cytokines • Pulmonary circulation • Pulmonary edema • Heart failure

Received July 12, 2002; Revised October 23, 2002; Accepted December 12, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Pulmonary endothelium is an early upstream hemodynamic target of left ventricular dysfunction in congestive heart failure (CHF) [1,2]. Decreased shear stress as a consequence of the left ventricular diastolic dysfunction [3], leads to a modification of endothelial cell biology in the pulmonary circulation, including decreased endothelial nitric oxide (eNO) synthase activity [1] and angiotensin converting enzyme expression and activity [4,5] as well as increased endothelin synthesis and secretion [6,7]. The model of anterior interventricular coronary artery ligature-induced left ventricular infarct and dysfunction is associated with an increased left ventricular end diastolic pressure [3,8], and an elevation of vascular pressure and dimensions in the left atria as well as in the pulmonary circulation [1,8]. At a defined post-infarct delay, the heterogeneity of the scar length and remodelling [3,9] gives the unique opportunity to study different degrees of left ventricular dysfunction, from compensated to decompensated stages of heart failure.

Interleukin 6 (IL-6) production is reported to increase in patients with CHF [10,11]. IL-6 is a pro-inflammatory cytokine which can be synthesized by endothelial cells [12]. It has been shown that endothelin could induce ET-A receptor-mediated IL-6 production by endothelial cells [13]. Pulmonary endothelin secretion is increased in CHF whereas the expression of endothelial clearance receptor ET-B is decreased, leading to an increase in circulating endothelin [6]. ET-B downregulation can enhance actions of endothelin-1 (ET-1) mediated by ET-A on the endothelium [14–16]. Conversely IL-6 enhances endothelin expression and secretion by endothelial cells in vitro [17]. IL-6 has also been attributed to increased endothelial permeability [18].

In the present study, we tested the hypothesis that dysfunctional pulmonary endothelium is a source of synthesis and storage of IL-6 in experimental CHF. To investigate this point, we evaluated the expression of IL-6 and the IL-6 receptor (IL-6R) in lung parenchyma in comparison to aorta and left ventricular myocardium of rats with experimental myocardial infarction (MI). We observed an up-regulation of IL-6 and a downregulation of IL-6R expression, and increased IL-6 peptide content as well as an endothelial localization of IL-6 storage in the lung proportional to the degree of heart failure. This increase in synthesis and storage of IL-6 was associated with NF-{kappa}B activation in the lungs of heart failure rats.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Experimental design
Normotensive male Wistar rats (Charles River, France) weighing 300 g were used. Infarction of the left ventricle (LV) was obtained by ligature of the left descending coronary artery under artificial ventilation [19] and general anesthesia (1 ml/kg Ketamine (Imalgène 500, Merial) and 0.5 ml/kg Xylazine (Rompun 2%, Bayer) intraperitoneally). Sham operated rats underwent the same surgical procedure with the exception of coronary ligature. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health (NIH publication No. 85-23, revised 1996).

Three months following coronary ligature the rats were killed. Blood was collected in 10 ml prechilled tubes on citrate (11 mM) and the plasma separated by centrifugation at 2500 rpm for 10 min at 4 °C, and stored at –20 °C. Pleural effusions were collected by needle aspiration, their volume measured by gravimetry, and frozen at –20 °C. The heart was excised and weighed. The LV was then separated from the rest of the heart (i.e. right ventricle and the two atria) and weighed. After excision, lung, thoracic aorta and LV myocardium were rinsed in cold phosphate-buffered saline, frozen in liquid nitrogen and stored at –80 °C.

2.2. Infarct size determination
MI size was measured in 34 rats using the techniques previously described by Chien et al. [5,20]. Presence of a pleural effusion was the essential criteria for the classification of MI rats as being decompensated. This classification was confirmed by a corresponding increase in the right heart (total heart weight minus that of the LV) to body weight ratio [9].

2.3. Evaluation of mRNA expression by RT-PCR
Total RNA was extracted from lung, thoracic aorta and LV tissues using the method described by Chomcynski and Sacchi [21]. The quality of the isolated RNA was verified by agarose gel electrophoresis. IL-6, IL-6R, tumor necrosis factor alpha (TNF{alpha}), gp130 and GAPDH expression were evaluated by semiquantitative RT-PCR as previously described [22]. Briefly, for RT 100 ng of total lung RNA, 400 ng of total thoracic aorta RNA and 1 µg of total LV RNA were primed with 1 µg oligo (dT) and incubated with M-MLVRT. The cDNA was amplified by PCR (Techne) using specific 33P-labeled oligonucleotide primers (Table 1).


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  		Table 1 PCR primer sequences

 
PCR fragments were separated by gel electrophoresis and revealed by ethidium bromide staining. Bands were cut out, dissolved and counted. PCR amplification was verified to be exponential, and the amplification products were proportional to sample input. IL-6, IL-6R and TNF{alpha} mRNA expression was expressed as the ratio of specific to GAPDH mRNA counts per minute.

2.4. Immunohistochemistry
Frozen sections were used for IL-6 immunohistochemistry. Sections (9 µm) were fixed in ice-cold acetone then rinsed with 0.05 M Tris (pH 7.4) before a 20 min incubation with 5% rabbit serum. The primary antibody (goat anti-IL-6, Tebu) was applied (dilution of 1/80 in 5% goat serum) for 30 min. Sections were again rinsed, then incubated with a polyclonal biotinylated anti-goat antibody (1/50 in 5% rabbit serum, Amersham) for 30 min. Following a 30 min incubation with anti-strepavidine–biotin–peroxydase (1/400, Amersham), revelation was performed using AEC (Dako).

2.5. IL-6 concentration determination
IL-6 levels in pleural effusion and tissue extracts were determined using a commercially available sandwich ELISA kit (R&D Systems, Parameter, Minneapolis, USA) following the manufacturer's instructions. Lung tissue IL-6 was extracted by homogenization of 100 mg of tissue in 1 ml PBS. The homogenate was then centrifuged at 5000xg for 20 min at 4 °C. An aliquot was used for total protein measurement (Bio-Rad, Hercules, California, USA). Results were expressed as picograms per milligram total protein.

2.6. Western Blotting analysis
Lungs were homogenized in lysis buffer (10 mM Tris–HCl pH 7.4, 1% Triton X-100, 0.5% NP-40, 0.5 mM orthovanadate, 150 mM NaCl, 1 mM EDTA, 1 mM NaF, 30 mM sodium pyrophosphate, 1 mM PMSF, 1 µg/ml leupeptin and 15 g/ml aprotinin) with a glass–glass homogenizer. The crude extract was centrifuged for 20 min at 14 000xg. Proteins (25 µg for I{kappa}B and 25 µg for IL-6) were submitted to SDS-PAGE and transferred to a polyvinylidene difluoride membrane (NEN). The membranes were incubated with antibodies against IL-6 (1/500, biotinylated anti-rat antibody, R&D Systems) and I{kappa}B{alpha}/I{kappa}Bβ (1/3000, polyclonal rabbit anti-mouse antibodies, Santa Cruz Biotechnology). Immunodetection was performed using chemoluminescence Renaissance reagents (NEN).

2.7. Electrophoretic mobility shift assay
Nuclear proteins from the lung were extracted as previously described [23]. Briefly, frozen lung tissue was homogenized in cold hypotonic lysis buffer (10 mM Hepes, 10 mM KCl, 1.5 mM MgCl2, 1 mM PMSF, 1 µg/ml leupeptine, 15 g/ml aprotinine and 0.4% NP-40) with a glass–glass homogenizer. After centrifugation at 9000xg for 30 s, the pellet was washed in 20 mM KCl buffer (20 mM Hepes, 22% glycerol, 20 mM KCl, 1.5 mM MgCl2, 0.2 mM EDTA, 1 mM DTT, 1 mM PMSF, 1 µg/ml leupeptin, 15 g/ml aprotinin). The pellet was resuspended in 600 mM buffer (same as above but with 600 mM KCl). Nuclear proteins were extracted by gentle agitation at 4 °C for 30 min and aliquots of the supernatants were made. Gel shift assays were performed with a commercial kit according to the manufacturer's instructions (Promega). Nuclear lung proteins (10 µg) were incubated with the labeled (32P)-NF-{kappa}B oligonucleotide. Nucleoproteinologonucleotide complexes were resolved by electrophoresis. The specificity of the binding was determined by incubating the same sample with a 100-fold molar excess of unlabeled NF-{kappa}B oligonucleotide.

2.8. Statistical analysis
Results are expressed as the mean±S.E.M. The group differences for each biological parameter were evaluated by ANOVA and, when the F test score was positive, a Scheffe test was performed to test the significance of the differences between groups. These analyses as well as regression curves and correlation coefficients were determined using the STATVIEW software package. All alpha levels were set at 0.05 and statistical significance was accepted for P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Degree of heart failure
A total of 18 rats with decompensated HF (severe MI), 16 with compensated HF (moderate MI) and 10 sham rats were used. There was no significant difference in body weight between the groups (Table 2). Both the heart weight and the heart weight to body weight ratio (heart weight index) were significantly increased in the decompensated rats as compared to both compensated and sham operated rats. The right heart weight index was also significantly increased in decompensated HF rats.


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  		Table 2 Body weight and heart parameters

 
3.2. IL-6, IL-6R, TNF-{alpha} and gp130 mRNA expression
The expression of IL-6 mRNA was significantly increased in the lung of rats with decompensated HF (0.18±0.02 in sham, 0.32±0.06 in compensated and 0.62±0.05 in decompensated rats, P<0.0001) (Fig. 1). The lung expression was related to the degree of heart failure and was positively correlated with the right heart weight index (r=0.63, F=27, P<0.0001).


Figure 1
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  		Fig. 1 Expression of mRNA in the lung tissue as determined by RT-PCR. IL-6, interleukin 6. **P<0.01 vs. sham, ***P<0.0001 vs. sham.

 
In contrast, aortic and left ventricular myocardial expression of IL-6 mRNA did not differ between the experimental groups. The expression of TNF{alpha} mRNA in the lung did not change (0.58±0.06 in sham, 0.64±0.08 in compensated and 0.60±0.06 in decompensated rats, NS).

IL-6R mRNA expression was significantly decreased in the lungs of the rats with decompensated HF (0.57±0.05 in sham, 0.46±0.05 in compensated and 0.38±0.03 in decompensated rats, P<0.01) while gp130 mRNA expression remained unchanged (1.07±0.1 in sham, 0.90±0.07 in compensated and 1.05±0.2 in decompensated rats).

3.3. IL-6 concentration and localization in the lung
IL-6 peptide content as determined by ELISA and Western Blot in the lung tissue was 2-fold higher in decompensated HF as compared to control rats (2.54±0.2 in sham, 2.88±0.44 in compensated and 5.03±0.4 pg/mg total protein in decompensated rats; ELISA, P<0.0001) (Fig. 2a). The changes in lung IL-6 concentration were closely correlated with the right heart weight index (r=0.85, F=28.7, P<0.001) (Fig. 2b). IL-6 peptide was also present in the pleural effusion of decompensated heart failure rats and was positively correlated with the expression of IL-6 mRNA in the lungs of decompensated HF rats (r=0.74, F=5, P<0.05). These data were confirmed by immunohistochemistry showing a preferential venous endothelial localization of IL-6 in the CHF lung (Fig. 3). IL-6 in the plasma was below the limit of detection by ELISA.


Figure 2
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  		Fig. 2 (a) Lung IL-6 levels as determined by ELISA (above) and representative Western Blots (below). (b) Regression analysis of IL-6 levels in the lung as determined by ELISA with respect to right heart weight index (r=0.85, F=28.7, P<0.001). ***P<0.0001 vs. sham.

 


Figure 3
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  		Fig. 3 IL-6 immunohistochemistry in the pulmonary endothelium (A) sham and (B) decompensated rats. Magnification 100x.

 
3.4. NF-{kappa}B activation in the lung
Because NF-{kappa}B could be one of the regulating factors of IL-6 expression, we explored the nuclear translocation of NF-{kappa}B and the cytosolic degradation of I{kappa}B in the lung of CHF rats. The amount of I{kappa}B{alpha} and I{kappa}Bβ proteins significantly decreased in the lung in proportion to the severity of CHF (I{kappa}Bβ: 5538±691 in sham, 3769±385 in compensated and 461±50 in decompensated rats, P<0.01, I{kappa}B{alpha}: 6077±695 in sham, 3154±372 in compensated and 538±62 in decompensated rats, P<0.01) (Fig. 4a). Fig. 4b shows that nuclear translocation of NF-{kappa}B was increased in the lung of HF rats. The shifted bands were specific for NF-{kappa}B since the addition of 100-fold excess unlabeled NF-{kappa}B oligonucleotide abolished the band.


Figure 4
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  		Fig. 4 NF-{kappa}B and I{kappa}B{alpha} and I{kappa}Bβ in the lung. (a) Western Blot (above) and quantification (optical density) of I{kappa}B{alpha} and I{kappa}Bβ (below) expression in arbitrary units. (b) NF-{kappa}B activity as determined by electrophoretic mobility shift assay. **P<0.01 vs. sham.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Experimental MI in the rat increases left ventricular diastolic pressure [3]. One of the immediate consequences is an increase in pressure and dimensions and a decrease in shear stress in the pulmonary circulation, leading to changes in pulmonary endothelial cell biology. Previous studies in our laboratory have shown such diverse examples of endothelial dysfunction in experimental CHF as up-regulation in the endothelinenergic system [6] and cyclic GMP secretion [24], contrasting with downregulation of eNO synthase [1] and angiotensin converting enzyme expression and activity [4,5].

Therefore, because the lung is an organ particularly rich in endothelial cells directly subjected to the hemodynamic resultants of a failing LV myocardium [1], and because endothelial cells are capable of synthesizing and secreting IL-6, we sought to test the hypothesis that IL-6 expression is upregulated in the lung and that the pulmonary endothelium could be a major source of synthesis and storage of IL-6 in a rat model of coronary artery occlusion-induced experimental heart failure.

Clinical trials have shown that circulating IL-6 levels are increased in MI patients [10,25,26] and that elevated IL-6 levels are a predictor of mortality [27]. Indeed, the determination of plasma IL-6 increased the predictive sensitivity of the NYHA score in humans [28]. We were, however, unable to detect an elevation in the plasma IL-6 concentration in our CHF rats. This could be explained by the fact that rats were sacrificed 3 months following infarction. Guillen et al. showed that plasma IL-6 levels increased 6 h following infarction in patients, but returned to baseline levels within 24 h [29].

In contrast, it is apparent that the lung secretes IL-6 in MI rats. The pleural effusion from CHF rats tested positive for IL-6, and this in proportion to the IL-6 mRNA expression in the lung. The presence of IL-6 in the pleural effusion and not in the plasma could be a result of the accumulation that occurs in the former as well as the significant dilution that occurs in the latter. Another possibility is that IL-6 in the plasma may well be principally found in high molecular mass complexes and therefore not detectable using the present ELISA kit. The formation of these complexes (up to 400–500 kDa) may modulate not only the immunoreactivity in vitro but also the bioavailability of circulating IL-6 in vivo, thereby providing another level of cytokine regulation [30].

The only tissue tested in this study that presented an increase in IL-6 mRNA was the lung. In particular, we did not observe up-regulation of IL-6 mRNA expression in the remaining myocardium of HF rats. These data are concordant with a recent report of the absence of significant IL-6/IL-6R mRNA modification in the human myocardial tissue of terminal heart failure patients [31], but contrasts with another report showing the inverse result also in human subjects [32]. We found that this increase in IL-6 mRNA was associated with that of the nuclear transcription factor NF-{kappa}B. NF-{kappa}B, in synergy with NF-IL6 [33] has been shown to increase IL-6 mRNA expression. Although commonly associated with the inflammatory cascade wherein TNF{alpha} increases IL-6 expression, TNF{alpha} mRNA was not increased in our model. Although not evaluated in the present study, we [1,8] and others [34,35] have previously detailed the hemodynamics in the LV and in the pulmonary circulation in this particular model. Atrial natriuretic peptide and endothelin gene expression is proportional to the hemodynamic parameters and their morphological consequences on the left myocardium and right heart weight due to the initial heterogeneity of the infarct length. We can therefore reasonably hypothesize that hemodynamic modifications in the pulmonary circulation may play an important role in the production of IL-6. The humoral factor in association with the decrease in shear stress, responsible for this augmentation of NF-{kappa}B could well be endothelin. In defense of this hypothesis Browatzki et al. have shown that ET-1 increases NF-{kappa}B levels via the ET-A receptor [36]. Similarly, Xin et al. [13] have shown that ET-1 induced an increase in IL-6 synthesis and secretion by cultured endothelial cells and that this was dependent of ET-A receptors. Our laboratory [6] has previously shown that the CHF lung presents a significant increase in both preproET-1 mRNA as well as the ET-1 peptide and a decrease in ET-B receptor expression, potentially enhancing the ET-A response. This was the case uniquely in the lung tissue (and not in the aorta or LV), concordant with the results of the current study concerning IL-6.

The downregulation of the IL-6R in the lung suggests also an excess of ligand [37,38] concurrent with the accumulation of IL-6 in the pulmonary endothelium as demonstrated by the increase in tissue IL-6 concentration and immunohistochemistry. That IL-6 downregulates IL-6R expression has been largely documented in other cell systems such as melanoma cells [39]. Contrasting with the downregulation of gp80 (IL-6R) the signal transducer associated protein gp130 expression was not modified in response to IL-6 [40], as seems to be the case in the present study.

Finally, because IL-6 has been shown to modulate endothelial permeability [18], the question remains as to the implication of IL-6 in the development of pulmonary edema characteristic of CHF.


   Acknowledgements
 
This study was supported by INSERM and by the Fondation de France.


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

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