© 2008 European Society of Cardiology
Interleukin-10 improves left ventricular function in rats with heart failure subsequent to myocardial infarction
Department of Cardiology, University of Erlangen-Nuremberg Erlangen, Germany
* Corresponding author. Department of Cardiology/Medical Clinic II, University of Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany. Tel.: +49 91 31 853 5000; fax: +49 1212 5 107 908 84. E-mail address: ch.stumpf{at}web.de (C. Stumpf).
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Evidence has shown that pro-inflammatory cytokines, especially TNF-
, are involved in the inflammatory response in the remodelling process after myocardial infarction (MI). Although IL-10, an anti-inflammatory cytokine, has been shown to antagonize some of the deleterious effects of TNF-, little is known about its role in post-MI left ventricular (LV) dysfunction. The aim of the present study was to investigate whether a therapy with rhIL-10 could be beneficial in an animal model of post-MI heart failure (HF).
Rats with experimental MI were treated with rhIL-10 (75 mn;g/kg/d sc) starting directly after MI induction, and continuing for 4 weeks. Controls were untreated MI and sham-operated rats. Cardiac function was assessed by echocardiography and cardiac catheterization 4 weeks after MI induction. Membrane-bound and soluble fractions of TNF-, IL-6 and IL-10, the ratio of TNF- to IL-10, serum levels of MCP-1 as well as myocardial macrophage infiltration, were analyzed. Treatment with rhIL-10 significantly improved post-MI LV function (FS +127%;, dP/dtmax +131%; LVEDP–36%). This effect was associated with a significant decrease in pro-inflammatory cytokine and chemokine levels (TNF-, IL-6, MCP-1) and furthermore resulted in a reduced myocardial infiltration of macrophages.
Key Words: Interleukin-10 • Myocardial infarction • Heart failure • Inflammation
Received May 18, 2008; Accepted June 12, 2008
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Despite intense research activities the mortality rate from heart failure (HF) still remains at a very high level. Comparing one-year survival rates for HF with those for a number of common cancers shows that prognosis from heart failure is still relatively poor: the one-year survival rate for HF is worse than those for breast, prostate or bladder cancer [1].
Over the past decade there has been increasing interest in the role of inflammatory mediators in HF. Elevated circulating levels of cytokines, in particular tumour necrosis factor (TNF)- and interleukin (IL)-6, have consistently been identified in patients with HF [2]. Studies such as the SOLVD trial showed an increased rate of mortality with increasing levels of TNF- in patients with chronic HF (CHF) [3].
Although inflammatory mediators have become a focus of interest in leading heart failure trials, little is known about the role of anti-inflammatory cytokines in CHF.
IL-10 is an anti-inflammatory cytokine with broad immunoregulatory activity, impacting on both the innate and cell-mediated branches of the immune system. It is produced by various inflammatory cells, especially macrophages and T-cells, and is a major inhibitor of cytokine synthesis; it suppresses macrophage function and inhibits the production of pro-inflammatory cytokines as well as matrix metalloproteinases, all of which have previously been described as important mediators in CHF [4].
IL-10 is seen as a natural antagonist to TNF- by inhibiting nuclear factor kappa B (NF-
B) signalling through the preservation of inhibitory factor kappa B (IB) [5].
In atherosclerosis as a chronic inflammatory disease, IL-10 has already been described as having protective properties in delaying disease progression with high levels of expression being associated with significantly decreased cell death and inducible nitric oxide synthase (iNOS) expression [6]. Decreased serum levels of IL-10 have been reported in patients with unstable angina further suggesting its protective role in chronic inflammatory disease conditions [7].
In HF patients, Bolger et al. have shown that IL-10 inhibited TNF- release from peripheral blood mononuclear cells (PMBC) isolated from patients with CHF [8].
Previously, we could have shown that patients with advanced CHF have significantly decreased serum IL-10 levels. In particular, NYHA class III and IV patients had significantly higher TNF-/IL-10 ratios suggesting that low IL-10 levels may favour a more inflammatory milieu [9].
Because of its anti-inflammatory potential, IL-10 is a strong candidate for therapeutic interventions. So far, IL-10 has already been tested in chronic inflammatory diseases, where a dominating role of TNF- is assumed (e.g. rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and cardiac allograft rejection) [5]. Exogenous administration of IL-10 was shown to protect against TNF- mediated oxidative stress-induced acute lung injury [10]. In a murine model of experimental viral myocarditis, Nishio et al. showed that treatment with recombinant IL-10 attenuated myocardial lesions [11]. In addition, a clinical study by Gullestad et al., in which CHF patients were treated with intravenous immunoglobulin, demonstrated increased IL-10 levels and improved left ventricular ejection fraction (LV-EF) [12].
On the basis of these data, we hypothesize that treatment with IL-10 is beneficial in heart failure subsequent to myocardial infarction. Therefore, we examined whether short-term treatment with rhIL-10 improves LV function in rats with heart failure subsequent to myocardial infarction.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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2.1. Animals
Male Sprague-Dawley rats were maintained on standard rat chow and water ad libitum. Myocardial infarction was induced by occlusion of the left anterior descending coronary artery (LAD). Sham control animals were similarly handled, except the suture around the coronary artery was not tied. Body weight, general behaviour, and mortality of the animals were monitored on a regular basis. Cardiac function was assessed 4 weeks after induction of MI or sham operation. All animal study protocols were approved by the local authority for Laboratory Animal Care.
2.2. Induction of myocardial infarction
Myocardial infarction was induced in adult male Sprague-Dawley rats by ligating the LAD according to the technique by Pfeffer et al. [13]. The rats were anaesthetized intraperitoneally with a mixture of xylazine (1 mg/100 g bodyweight) and ketamine (10 mg/100 g bodyweight), intubated with a fine polyethylene tube and put on positive-pressure ventilation (model 683, Harvard Apparatus, Inc., South Natick, MA, USA). A left intercostal thoracotomy was performed to expose the heart, and the pericardium was opened. The LAD was looped by a single nylon suture (5.0) 1 mm from its origin, and gently tied. This procedure produced a clearly demarcated (cyanotic and bulged) area of acute ischaemia corresponding to the distribution of the LAD distal to the occlusion, which results in MI of the free left ventricle and subsequently heart failure. After the ligature, the heart was repositioned in the chest, the skin was sutured, and air in the chest was removed with a syringe. After surgery, all rats were individually caged for a 24-h period of recovery. A sham-surgery group, in which all surgical procedures were the same, except for the LAD ligation, was studied and did not present any differences when compared to control rats (data not shown). After this period, all the infarcted rats recovered to good clinical condition, and exhibited no respiratory distress nor ascites, peripheral oedema, or pleural effusion.
2.3. Echocardiography
Echocardiographic examinations were performed under volatile isoflurane anaesthesia (2.5% in oxygen, 500-700 mL/min; Draeger, Luebeck, Germany and Foehr Medical Instruments, Seeheim, Germany). Care was taken to maintain a stable, physiological heart rate at approximately 350 bpm during the experiments, which was monitored using a 3 channel ECG. Chests were shaved and rats were placed in left lateral decubitus position. For echocardiographic examination we used a Vivid 7 ultrasound system (General Electric Healthcare, USA) comprising a 10-MHz transducer (General Electric, S10). All settings for pre- and post-processing were adapted and optimised for small animals: penetration depth was 2 cm, near field was focussed, and gain was adjusted to optimal delineation. All recordings were stored digitally for subsequent off-line analysis.
Examinations were started in conventional two-dimensional echocardiography (2DE) with a frame rate of 80 per second resulting in 14 frames per heart cycle. The scan was performed in a parasternal short axis view to measure left ventricular diameter and endocardial areas in end-diastolic and end-systolic frames as recommended by the American Society of Echocardiography [14]. The time of end-diastole was therefore defined as time of maximum diameter of the LV in one heart cycle. Accordingly, end-systole was defined as the minimum diameter. Subsequently, we calculated the fractional shortening (FS).
2.4. Haemodynamic measurements
The left ventricular pressures were measured via a saline-filled cannula, which was inserted through the right carotid artery and connected to a pressure transducer. The cannula was inserted into the left ventricle to monitor left ventricular systolic (LVSP) and left ventricular end-diastolic pressures (LVEDP) as well as to measure maximum rate of rise of LV pressure (dP/dt).
2.5. Heart tissue samples
After completing the cardiac haemodynamic measurements, the rat hearts were stopped in diastole by an intravenous injection of a 10% potassium chloride solution 2-3 mL. The right ventricles were separated from the heart at the septum. The hearts were immediately frozen in liquid nitrogen and stored at –70 °C.
2.6. Serum concentration of soluble cytokines
Serum levels of IL-10, TNF-, IL-6 and MCP-1 were measured using commercially available ELISA kits [R&D Systems, Minneapolis, MN; USA and Invitrogen Corporation, Carlsbad, CA, USA (for MCP-1)]. All kits had the following sandwich ELISA format: microtitre plates pre-coated with a murine monoclonal antibody against the rat cytokine being measured. Standards of the analyte and serum samples were added in duplicate, along with a second antibody against another epitope of the analyte conjugates to horseradish peroxidase (TNF-, IL-6, IL-10) or streptavidin peroxidase (MCP-1). The samples were incubated for 2 h. Finally, the chromogen tetramethyl benzidine was added and incubated for 20 min in the dark. After the addition of 1 M H2SO4, the absorbance at 450 nm was read and standard curves were plotted in a Spectramax Plus microplate reader (Molecular Devices, Munich, Germany). All assays were conducted by staff who were blinded to the clinical status of the individual subjects. The intra- and interassay coefficients of variation (CV) in our laboratory were below 9%.
2.7. Myocardial protein levels of IL-10, TNF- and IL-10
Hearts were washed with PBS. Viable ventricular tissue was flash frozen in liquid nitrogen. Frozen tissue (0.5-1.0 g) was homogenized, and membrane-bound fractions of TNF-, IL-6 and IL-10 proteins were collected and analyzed by ELISA using commercially available kits as described above [15,16].
2.8. Treatment with rhIL-10
MI rats were randomised to the treatment or MI control groups. Animals in the treatment group were treated with rhIL-10 (75 µg/kg subcutaneously (Sigma, St. Louis, USA)). RhIL-10 was administered daily beginning on the day of coronary ligation and continued for the next 4 weeks.
2.9. Histological examination of rat hearts
Hearts were stained with haematoxylin or subjected to immunostaining by using antibodies against CD68 (ED-1; Serotec). Immunoreactive materials were visualized using a streptavidin-biotin staining kit. Macrophages (CD68-positive cells) were counted by a technician blinded to the treatment regimen. As negative controls, immunohistostaining was performed without the first antibodies.
2.10. Statistical analysis
After a test of normality had been performed, variables with a skewed distribution were analyzed by non-parametric methods. For comparisons of groups, the Mann-Whitney U test and the Kruskal-Wallis one way variance test on ranks were performed. Coefficients of correlation (r) were calculated by the Spearman rank test. Statistical significance was considered to be indicated by a value of p<0.05. For our sample size and for alpha 0.05, analysis revealed a power of 0.92.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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The mortality in the coronary artery-ligated groups, during or immediately after the surgery, was about 25%. There was no significant difference in body weight gain between the coronary artery-ligated animals and their respective sham-operated controls. In the rhIL-10-treated MI group, body weight was not different from the non-treated MI group (Table 1).
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3.1. Echocardiography and haemodynamic measurements
Echocardiographic measurements and left heart catheterization were performed 4 weeks after surgery (Tables 1 and 2). In the untreated group, MI resulted in a progressive increase in LV diameter which was slightly but not significantly reduced by rhIL-10 (9.6±0.4 vs. 8.9±0.7, p=ns). LV function in the MI group showed a progressive and significant impairment after MI as indicated by a decrease in fractional shortening, which was significantly prevented by treatment with rhIL-10 (Table 2).
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In the untreated MI group, dP/dt as an index of myocardial contractility as well as the LVSP was significantly reduced compared to the sham-operated group. LVEDP, on the other hand, was significantly increased (Table 1, Fig. 1). Treatment with rhIL-10 significantly improved LVSP, dP/dt and reduced LVEDP.
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p<0.05 and 
p<0.01 rhIL-10 treatment vs. untreated MI group.3.2. Inflammatory and anti-inflammatory cytokines in post-infarct LV dysfunction
Four weeks after coronary artery ligation, levels of membrane-bound TNF-
as well as membrane-bound IL-6 were significantly increased (Fig. 2; membrane TNF-: 22.3±6.9 pg/mg vs. 9.8±4.3 pg/mg, p<0.01; membrane IL-6: 154.2±47.2 pg/mg vs. 91.2±49.6 pg/mg, p<0.01). Systemically, serum levels of TNF-, IL-6 and MCP-1 were also found to be significantly increased in the untreated MI group as compared to the sham-operated controls (Fig. 2; TNF-: 15.8±8.1 pg/mL vs. 4.3±2.7 pg/mL, p<0.01; IL-6: 135.4±52.3 pg/mL vs. 56.2±32.4 pg/mL, p<0.01; Fig. 5 MCP-1: 350.4±44.3 pg/mL vs. 89.6±22.2 pg/mL, p<0.01). On the other hand, the anti-inflammatory cytokine IL-10 was significantly decreased in its membrane-bound as well as its soluble form 4 weeks after MI induction (Fig. 3; membrane IL-10: 4.3±2.7 pg/mg vs. 14.3±4.3 pg/mg, p<0.01; soluble IL-10: 0.8±0.4 pg/mL vs. 3.1±0.8 pg/mL, p<0.01). When comparing the inflammatory to the anti-inflammatory ‘profile’ in the MI group, the ratio of TNF- to IL-10 was found to be significantly higher in the MI group (Fig. 4, 3.1±0.8 vs. 0.8±0.4, p<0.01).
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p<0.01 vs. MI rats;
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Treatment with rhIL-10 at a dose of 75 µg/kg bodyweight significantly decreased membrane-bound and soluble levels of TNF-
as well as IL-6 compared to the untreated MI group (Fig. 2; serum TNF-: 15.8±8.1 pg/mL vs. 9.3±6.7 pg/mL, p<0.01; serum IL-6: 135.4±52.3 pg/mL vs. 76.4±23.2 pg/mL, p<0.01; membrane TNF-: 22.3±6.9 pg/mg vs. 15.9±7.6 pg/mg, p<0.05; membrane IL-6: 154.2±47.2 pg/mg vs. 91.2±49.6 pg/mL, p<0.01). A similar effect was seen for the CC chemokine MCP-1, which was significantly decreased by treatment with exogenous IL-10 (Fig. 5; MCP-1: 350.4±44.3 pg/mL vs. 123.7±76.5 pg/mL, p<0.01).
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3.3. Myocardial infiltration of macrophages
Macrophages are key regulators of the early LV remodelling process after MI. To determine the rate of macrophage infiltration post-MI, the number of macrophages infiltrated into the infarct zone was quantified (Fig. 5). The myocardium of non-treated MI rats had significantly stronger infiltration of macrophages as compared to rhIL-10-treated MI rats (ED-1: 52.3±14.5 cells/mm2 vs. 40.6±9.3 cells/mm2, p<0.05).
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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The major novel finding of our study was that treatment with rhIL-10 significantly improved LV function in rats with heart failure after experimental MI. This effect was associated with a decrease in the inflammatory cytokines TNF-
and IL-6, a decrease of the chemokine MCP-1 and a reduction of myocardial macrophage infiltration.
IL-10, initially designated cytokine synthesis inhibitory factor (CSIF), was originally identified as a product of macrophages and lymphocytes of the Th2 subtype. It inhibits many cellular processes that have already been shown to play important roles in MI, such as production of matrix metalloproteinases and cytokines, activation of NF-B as well as apoptosis and cell death [17]. IL-10 represents a substantial suppressor of cellular immunity [18]. Data from investigations of the effects of IL-10 on immune cells, suggest that the major physiological importance of IL-10 seems to be the limitation of inflammation. This hypothesis was further confirmed by experimental research in IL-10 knockout mice, as well as by the effects of IL-10 observed in several inflammatory, autoimmune, and tumour models.
IL-10 deficient mice develop lethal inflammation of the intestine, which can be stopped by application of IL-10 [19]. Interestingly, IL-10 deficient mice, if grown under conditions that avoid inflammatory bowel disease, typically develop enhanced formation of atherosclerotic vascular lesions [20]. This anti-atherogenic effect of IL-10 has also been supported by in vitro findings. IL-10 inhibits adhesion of monocytes to endothelial cells by down-regulating the adhesion molecules CD18 and CD62-L [21]. Furthermore, in vitro studies suggest complex and cell-type specific actions of IL-10 on expression of matrix metalloproteinases (MMP) and their inhibitors [22]. In a model of angiogenesis induced by murine hind limb ischaemia IL-10 has exerted angiostatic effects [23].
In a previous study exploring the role of IL-10 in post-infarction inflammation, Yang et al. demonstrated that reperfused infarction in IL-10 null mice was associated with a 75% mortality rate, whereas no death occurred in wild type animals [24]. Infarcted IL-10 null animals demonstrated larger infarct size and enhanced inflammation evidenced by increased plasma levels of TNF- and increased tissue expression of the intercellular adhesion molecule (ICAM)-1 [24]. In our animal model, the extent of post-MI heart failure significantly correlated with a decrease in the anti-inflammatory cytokine IL-10 and a significant increase in the pro-inflammatory cytokines TNF- and IL-6 as well as the CC chemokine MCP-1. In the progression of HF, the immunologic balance between pro- and anti-inflammatory cytokines changed in favour of a more inflammatory milieu as reflected by an increased ratio of TNF- to IL-10. These findings in rats correspond to our previous findings in patients with severe cardiac failure, where significantly decreased serum IL-10 levels and an increased TNF-/IL-10 ratio have been shown [9]. In accordance to these results Kaur and colleagues pointed out that even if TNF- levels are not elevated, a decrease of IL-10 can shift the balance towards the inflammatory direction. Interestingly, in their report this effect correlated with depressed cardiac function [25].
Further data have shown that improvement in cardiac function after treatment with losartan, growth hormone [26] or even after application of immunoglobulins [12] is associated with an increase in IL-10 and a decrease in TNF-, thus shifting the balance between pro- and anti-inflammatory cytokines towards the anti-inflammatory IL-10. Although these investigations suggested cardioprotective effects of IL-10 in HF, the potential role of treatment with exogenous IL-10 has not yet been investigated.
There are, however, some encouraging reports on the therapeutic use of IL-10 in chronic inflammatory diseases in which inflammatory mediators, such as TNF-, are believed to predominate, including inflammatory bowel disease psoriasis and rheumatoid arthritis [27]. Exogenous administration of IL-10 has already been shown to protect against TNF- mediated oxidative stress-induced acute lung injury, which was augmented by IL-10 antibody [10]. Other reports show effectiveness of IL-10 in animal models of arthritis, in reducing inflammation, cellular infiltrates, and joint destruction. Meanwhile it has been shown that IL-10 can even be beneficial in models of experimental autoimmune encephalomyelitis, pancreatitis, diabetes mellitus and experimental endotoxaemia [5]. Only recently, Nishio et al. showed attenuation of myocardial lesions by exogenous IL-10 in a model of experimental myocarditis [11]. In the present study, we showed that treatment with rhIL-10 correlated with reduced levels of the inflammatory cytokines TNF- and IL-6 and significantly improved LV dysfunction in heart failure rats subsequent to myocardial infarction. IL-10 treated animals furthermore had reduced levels of MCP-1 and showed reduced myocardial infiltration of mononuclear cells suggesting again a key regulatory role of IL-10 in orchestrating inflammatory responses following MI. These data are in accordance with a report by Yu et al., in which they showed amelioration of post-MI LV dysfunction by manipulating the balance between pro- and anti-inflammatory cytokines via central gene transfer of IL-10 [28]. Since the deleterious effects of TNF- seem to predominate in post-MI remodelling progressing to HF, our findings suggest that IL-10 may improve LV function by inhibiting TNF-.
In summary, our data support the concept that the balance between pro- and anti-inflammatory cytokines is a major determinant in the prognosis of post-MI heart failure and therefore, enhancing anti-inflammatory cytokines may be a promising approach for medical treatment. Since there is evidence that a genetically determined low IL-10 producer might have a poorer cardiovascular prognosis [29], it is tempting to hypothesize that these patients could benefit from a treatment which shifts the inflammatory balance towards the anti-inflammatory direction. However, further studies are needed to elucidate whether HF patients could benefit from therapy with IL-10 on the basis of their IL-10 plasma levels, whilst genotyping of IL-10 polymorphisms may identify patients who will benefit most.
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