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European Journal of Heart Failure 2001 3(5):517-526; doi:10.1016/S1388-9842(01)00156-8
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© 2001 European Society of Cardiology

A glossary of circulating cytokines in chronic heart failure

Stamatis Adamopoulos*, John T. Parissis and Dimitrios Th. Kremastinos

Second Department of Cardiovascular Medicine, Onassis Cardiac Surgery Center Athens, Greece

* Corresponding author. Zinonos 9, Halandri, 15234, Athens, Greece. Tel.: +30-16848463; fax: +30-19493373. E-mail address: elbee{at}ath.forthnet.gr (S. Adamopoulos)


   Abstract
Top
 Abstract
1. Introduction
 2. Cytokine glossary
 3. Conclusions
 References
 
Recent studies have emphasized the importance of biologically active molecules, termed cytokines, in the development and progression of the syndrome of chronic heart failure. This article summarizes a glossary of major cytokines and other cytokine-related inflammatory factors implicated in the pathophysiology of chronic heart failure, describing the source of their synthesis and factors regulating their secretion and analyzing their biologic effects on the cardiovascular system.

Key Words: Chronic heart failure • Cytokines • Inflammatory factors • Immune activation

Received December 14, 2000; Revised April 11, 2001; Accepted April 26, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Cytokine glossary
 3. Conclusions
 References
 
Cytokines are hormone-like peptides that play a very important role in the cellular interactions [1]. They participate in a wide range of biologic processes and their effects on the cardiovascular system include promotion of inflammation, intravascular coagulation, free-radical generation, endothelial injury and cardiomyocyte or endothelial cell apoptosis [2,3]. They are produced by the immunological as well as cardiovascular system structural cells [1,4]. Cytokines are pathogenic factors in many disorders, where inflammation etiology is suspected. Accumulating evidence indicates that these inflammatory mediators play an important role, not only in the pathogenesis of atherosclerosis [5] and in the cardiac dysfunction that accompanies systemic sepsis [6], viral myocarditis [7] and cardiac allograft rejection [8] but also in the syndrome of chronic heart failure (CHF) [3,9,10]. Thus, it has been suggested that an abnormal inflammatory response, including overexpression of proinflammatory cytokines, soluble adhesion molecules and chemoattractant factors, may be responsible for the progression and clinical deterioration of CHF [10,11]. Fig. 1 describes the inflammatory cascade implicated in the pathophysiology of CHF.


Figure 1
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  		Fig. 1 Schematic representation of inflammatory cascade implicated in the pathophysiology of CHF.

 
In the failing heart, elevated left ventricular end-diastolic wall stress causes myocardial expression of cytokines, which directly or indirectly influence left ventricular contractile performance and remodeling. When proinflammatory cytokines are overproduced within the myocardium, they can spill over into the peripheral circulation, where they are capable of secondarily activating the immune system [4,9]. Alternatively, raised plasma levels of cytokines in CHF may be the result of extramyocardial production because of altered tissue perfusion and tissue hypoxia, possibly enhanced by bacterial endotoxin release from the gut in the congestive condition of the syndrome [4,10]. In this article, we present a glossary of major proinflammatory cytokines and other cytokine-related inflammatory factors associated with the pathophysiology of CHF as evidenced by recent experimental and clinical data, and describe briefly their biologic effects on the cardiovascular system in the setting of CHF.


   2. Cytokine glossary
Top
 Abstract
 1. Introduction
 2. Cytokine glossary
3. Conclusions
 References
 
2.1. Tumor necrosis factor-{alpha} (TNF-{alpha})
This cytokine was originally identified for its potent toxicity against tumor cells, hence its name. The TNF-{alpha} molecule (a 157-amino acid polypeptide) exists as a membrane bound and a secreted molecule, both bioactive [12]. The activated macrophage is the main source of TNF-{alpha} containing both cell associated and membrane bound TNF-{alpha} [13]. Other cells releasing TNF-{alpha} include lymphocytes, fibroblasts, neutrophils, smooth muscle and mast cells [13]. Furthermore, adult mammalian myocardial cells are able to produce TNF-{alpha} after extracellular stimuli such as endotoxin, hypoxia or increased mechanical stress [14].

TNF-{alpha} acts at the cellular level via both type I (p55) and type II (p75) receptors (TNFRI and TNFRII) and recently, it has been suggested that TNFRI and TNFRII are present in the human myocardium [15]. TNF-{alpha} activates multiple transduction pathways, inducing or suppressing a wide variety of genes, including those encoding the production of other cytokines, adhesion molecules and inducible nitric oxide synthase (iNOS) [16]. Additionally, it orchestrates the inflammatory response through activation of proinflammatory cytokine (such as interleukin-1 and interleukin-6) genes, as well as its own production [16].

TNF-{alpha} effects on cardiac function are dependent from the amount and duration of cytokine expression. Short term expression within the heart may be an adaptive response to different forms of ‘stress’, whereas long term expression may be maladaptive by producing cardiac decompensation [17]. Excessive TNF-{alpha} levels can produce left ventricular dysfunction and cardiomyopathy and may be related with the clinical manifestations and the progression of CHF [18,19]. This proinflammatory cytokine participates in the pathophysiology of heart failure progress, at least partially, by stimulating myocyte hypertrophy through the generation of reactive oxygen intermediates in cardiac myocytes, by inducing ventricular remodeling through stimulating extracellular matrix protein production and increased turnover of matrix, by causing cardiomyocyte loss through necrosis and apoptosis, and by depressing myocardial function through the nitric oxide-dependent and sphingomyelinase pathways [20,21]. In addition, TNF-{alpha} overexpression causes skeletal myopathy and endothelial dysfunction in CHF patients through free radical and nitric oxide overproduction, leading to skeletal myocyte and endothelial cell apoptosis. These peripheral deleterious effects contribute significantly to further clinical deterioration of the syndrome [20,21]. Recently Mann's group has scheduled and administered a novel anti-TNF-{alpha} molecule, the Etanercept 75 (p75 Fc fusion protein), with beneficial effects on cardiac function and left ventricular remodeling in a small patient population with severe CHF [22,23]. However, to assess the long term effects of Etanercept, randomized, double-blind and placebo-controlled clinical trials (RENAISSANCE, RECOVER) are presently enrolling patients with NYHA class II–IV heart failure symptoms in the USA and other countries [20,22].

2.2. Soluble TNF receptors I and II (sTNFRI and sTNFRII)
The extracellular domain fragments of both TNF receptors shed from cell surfaces can be detected as soluble forms (sTNFRI and sTNFRII) in the urine and blood [24]. These soluble proteins are supposed to regulate the TNF-{alpha} bioactivity either by inhibiting the binding of TNF-{alpha} trimers to the membrane receptors or by preventing TNF-{alpha} trimers from dissociation to inactive monomers [24]. It has been shown that at physiological concentrations, sTNFRs may act as ‘slow-release reservoir’ of bioactive TNF-{alpha}, thus increasing its half life [25]. The stabilization of TNF-{alpha} by its soluble receptors is reminiscent of the stabilization of enzymes by their substrates. When present at higher concentrations, as in patients with severe CHF, sTNFRs could inhibit the pathological increase of TNF-{alpha} activity [4,26]. Under these conditions, sTNFRs could act as anti-TNF molecules by forming complexes with high affinity to the cytokine. The shedding of these receptors and the resultant decrease in their concentration on the cell surface could also prevent cell damage [27]. Alternatively, since TNF-{alpha} induces the shedding of its soluble receptors, it is possible that increased sTNFRs simply reflect activation of the cytokine at a local level [28].

Recently, it has been suggested that measurement of sTNFRs is essential for the evaluation of TNF-{alpha} activation in CHF [29]. Both sTNFRs are increased in severe CHF patients and might inhibit the in vitro cytotoxicity of TNF-{alpha} [30]. Finally, the increased levels of sTNFRII were significantly correlated with poor short-term prognosis of CHF patients [30].

2.3. Interleukin-6 (IL-6)
Interleukin-6 (IL-6) is another multifunctional cytokine, which mediates both immune and inflammatory responses. IL-6 is produced by a variety of different cell types including mononuclear phagocytes, some activated T-cells, vascular endothelial cells and fibroblasts [31]. Several studies [32–37] have consistently found elevated levels of IL-6 in the setting of CHF. Although, IL-6 may be locally produced in the myocardium, data suggest that IL-6 is peripherally released in CHF patients [34]. Although the mechanism for increased elaboration of IL-6 in CHF is not known, TNF-{alpha} is sufficient to induce IL-6 gene and protein expression in a variety of cell types, suggesting that there may be a ‘cytokine cascade’ in the setting of CHF [10,20]. Some investigators [35] have identified a significant correlation between elevated levels of TNF-{alpha} and elevated levels of IL-6 in severe CHF. In the report by Mac Gowan et al. [36], there was a statistically significant correlation between elevated levels of IL-6 and elevated right heart pressures of CHF patients. Finally, in a recent study [37], serum IL-6 was identified during follow-up of severe CHF patients as the most powerful independent predictor of new heart failure episodes, death or need for heart transplantation, a better predictor than TNF-{alpha}, plasma neurohormones or left ventricular function.

2.4. Soluble interleukin-6 receptor (sIL-6R)
Human IL-6 receptor is a glycoprotein with a molecular mass of 80 kDa. In contrast to the TNF receptors, the cytoplasmic domain of IL-6 is not necessary for intracellular signaling to occur. Moreover, IL-6 when bound to its receptor is known to associate with a second membrane glycoprotein with a molecular mass of 130 kDa (gp 130) [38]. The extracellular domain of human IL-6 receptor can be detected as soluble form (sIL-6R) into circulation of CHF patients [39,40]. The exact clinical significance of these findings in CHF remain uncertain. However, it has been postulated that mechanisms similar to those of TNF system overactivation may be responsible for sIL-6R release into circulation of CHF patients [39,40].

2.5. Interleukin-1 (IL-1)
Studies have shown that all mammalian species express two IL-1 related genes, IL-1{alpha} and IL-1β, which mediate systemic immune responses as well as the production of inflammatory responses via production of prostaglandins [2,41]. Although monocytes are the major source of IL-1, almost every cell type in the body can produce IL-1 under the appropriate conditions [2,3]. While there are few reports on the effects of IL-1 on myocardial function, some of them suggest that this cytokine is also capable of independently modulating myocardial function [3,10,16]. Furthermore, there is little clinical evidence that supports an elevation of IL-1 in CHF and an important role for this cytokine in the pathophysiology of the syndrome [10,39]. It has been reported that IL-1 can lead to uncoupling of the β-adrenoreceptor from adenylate cyclase, which has been postulated as one of the mechanisms responsible for the progression of CHF [10]. Thus, IL-1 may be a basal part of overactivated cytokine cascade in the setting of CHF [3,10,16].

2.6. Interleukin-1 receptor antagonist (IL-1ra)
There is a discrete inhibitor for the IL-1 receptor, the so-called IL-1ra, which antagonizes IL-1 for binding to its receptor and can, thus, attenuate, the effects of IL-1 [42]. IL-1ra is a member of the IL-1 gene family and its production from activated human monocytes increases under the same inflammatory conditions that stimulate IL-1{alpha} and IL-1β [43]. IL-1ra is often considered as more sensitive marker of IL-1 system activation than IL-1 levels and may be correlated better with the severity of various diseases with immune system activation (septic shock, coronary artery disease, CHF), in which IL-1 levels into the circulation are usually low [39]. On the other hand, given that IL-1ra is a specific antagonist of IL-1, elevated levels of IL-1ra could represent a suitable response to counteract the inflammatory process caused by IL-1 [44]. Finally, recombinant IL-1ra has been used for the blockage of IL-1 activity in various animal models of disease, including septic shock [45].

2.7. Interleukin-2 (IL-2)
Antigenic stimulants or proinflammatory cytokines (e.g. IL-1) induce the synthesis of IL-2 by T lymphocytes which in turn is an endogenous T-cell mitogen. IL-2 increases expression of its own receptor on T cells and markedly enhances T-cell proliferation [46]. As a result, this cytokine amplifies the immune response and dramatically expands the population of antigen-specific T lymphocytes. Furthermore, it stimulates, through the IFN-{gamma} production, the release of other inflammatory factors, such as TNF-{alpha} and GM-CSF, from activated macrophages [46]. Recent experimental and clinical data have shown that circulating IL-2 is actively implicated in the pathophysiology of myocarditis and idiopathic dilated cardiomyopathy, reflecting an abnormal T-lymphocyte activation in these disorders [7,46,47]. It has been reported that IL-2 serum concentrations were abnormally increased in idiopathic dilated cardiomyopathy patients and relatives with asymptomatic left ventricular enlargement as compared with those with ischemic cardiomyopathy [47]. On the other hand, the expression of IL-2 receptor after the stimulation with either concavalin A or anti-T3 monoclonal antibody was found to be reduced in patients with idiopathic dilated cardiomyopathy when the results were compared with those of normal controls [48]. A significant correlation was noticed between the expression of IL-2 receptor and the left ventricular end-diastolic pressure, suggesting that IL-2 system and subsequent T-lymphocyte activation abnormalities may be associated with pathogenesis and hemodynamic deterioration of idiopathic dilated cardiomyopathy [48].

2.8. Soluble IL-2 receptor (sIL-2R)
Extracellular domain of T-lymphocyte IL-2 receptor is the circulating sIL-2R [46]. It has been reported that high levels of circulating sIL-2R do not neutralize the actions of IL-2 but are a sensitive marker for the interaction of the cytokine with its target cells and reflect the cellular autoimmune activation and especially T-lymphocyte-dependent tissue injury in various inflammatory diseases including myocarditis and idiopathic dilated cardiomyopathy [49]. High serum sIL-2R levels were also correlated with the clinical deterioration of patients with CHF due to idiopathic dilated cardiomyopathy, as well as were identified as significant independent predictors of death or need for heart transplantation in the same population [50].

2.9. Soluble Fas (sFas)
Fas/APO-1 is a 45-kDa type I membrane protein that belongs to the tumor necrosis factor receptor superfamily and mediates apoptosis when cross-linked with a specific agonistic antibody or Fas ligand (Fas L) [51]. Cardiomyocytes might cleave and release the extracellular domain of this apoptosis-signaling molecule into circulation as a consequence of apoptosis [52]. This soluble form of Fas (sFas) may block the action of inducer of apoptotic cell death, Fas L [52]. Elevated levels of apoptosis mediator sFas were found in the serum of patients with autoimmune diseases [53], myocarditis [54] and severe CHF [52], suggesting that Fas/FaL system may play an important role in the regulation of peripheral immune responses in these disorders. Recent studies [52,55] have also shown that the peripheral overactivation of the Fas/FasL system, as expressed by elevation of Fas soluble forms, may be related with the degree of left ventricular remodeling and have prognostic value in CHF.

2.10. Soluble Fas ligand (sFas L)
Fas L, a TNF-{alpha} related cytokine, is synthesized as a membrane-bound protein that can be converted by proteolytic cleavage into a soluble form (26 kDa glycoprotein) that is then released into circulation [52]. In many cell types including human cardiomyocytes and endothelial cells, cross-linking of Fas with sFasL is followed by intercellular Ca2+ homeostasis alterations, caspase activation, apoptotic gene transcription and, finally, apoptotic cell death [56]. This sFasL-induced apoptotic process is closely related with the progression of CHF. A recent study has also demonstrated that elevated plasma levels of sFasL were significantly correlated with the severity of symptoms and functional status of CHF patients [57].

2.11. Macrophage chemoattractant protein-1 (MCP-1)
MCP-1 is a low-molecular-weight protein characterized by its ability to induce directional migration of leukocytes and thought to play an important role in controlling inflammation and immune responses. It is a member of the largest chemotactic cytokine subfamily, called C–C chemokines; this class of chemokines does not have an amino acid separating the first two N-terminal cysteine residues [58]. The involvement of chemokines in the pathogenesis of atherosclerosis has been widely investigated, and its central role in this process has been clearly clarified [59–61]. Recently, Aukrust et al. [62] have reported that circulating levels of MCP-1 were increased in patients with CHF and have suggested that it was involved not only in the pathogenesis of atherosclerosis and ischemia-induced myocardial injury, but also in the development of CHF. In this study [62], the elevated levels of MCP-1 in CHF were correlated with the degree of left ventricular dysfunction, as well as with enhanced circulating monocyte activity and increased oxidative stress. On the other hand, experimentally, it has been suggested [63] that mechanical overload induces the myocardial expression of MCP-1, which attracts and activates monocytes and macrophages, and that these recruited cells produce proinflammatory cytokines which contribute to the pathogenesis of CHF [64].

2.12. Macrophage inflammatory protein-1{alpha} (MIP-1{alpha})
MIP-1{alpha} is also a C–C chemokine produced by various types of inflammatory cells [58,60]. MIP-1{alpha} has chemotactic activity for both monocytes and lymphocytes and may be a major signal for the accumulation of mononuclear leukocytes in inflammatory diseases [60]. Aukrust et al. [62] have found that plasma activity of MIP-1{alpha} was significantly elevated in patients with CHF, with particularly high levels in patients with the most severe CHF evaluated both clinically (NYHA class IV) and hemodynamically (low ejection fraction). According to these observations, it is tempting to hypothesize that enhanced C–C chemokine levels, possibly in combination with other proinflammatory cytokines, may be an important factor in mediating the infiltration and activation of mononuclear leukocytes into the myocardium of CHF patients, thereby playing an important pathogenic role in the development of CHF.

2.13. Regulated on activation normally T-cell expressed and secreted (RANTES)
RANTES is a C–C chemokine produced by inflammatory cells and platelets, and regulates T-lymphocyte activation in various inflammatory diseases including atherosclerosis [65]. In addition to its growth promoting and chemotactic effects on T-lymphocytes, this cytokine may also modulate other functions of this cell population such as free radical generation and production of other cytokines [66]. It has been postulated that RANTES, through the above mechanisms and vicious circles derived from platelet–inflammatory cell interactions, is elevated in CHF patients with the most severe symptoms (NYHA class IV) and may actively participate in the pathophysiologic events of advanced CHF [62]. However, these findings warrant further studies investigating the possible pathogenic role of RANTES in the development and progression of CHF.

2.14. Interleukin-8 (IL-8)
IL-8 is a member of the other major chemotactic cytokine subfamily called C–X–C chemokines (a class of chemotactic cytokines with one amino acid separating the first two N-terminal cysteine residues) [58]. Recent studies suggest that IL-8 may be involved in the pathogenesis of various heart diseases. Reperfusion of ischemic myocardium promotes influx of neutrophils involving IL-8 as an important contributing mediator [67]. Furthermore, a potential role in atherogenesis of IL-8, through stimulation of IL-8 receptor CXCR-2, is receiving increasing attention [68], while there are some reports on raised IL-8 levels in patients with cardiogenic shock [69]. Damas et al. [70] also showed that circulating levels of IL-8 and other C–X–C chemokines, gradually increased in patients with CHF in parallel with an increase in NYHA functional class. Although IL-8 and other C–X–C chemokines may be produced by a variety of cells (e.g. T-cells, neutrophils, fibroblasts, endothelial and vascular smooth muscle cells), the findings of this study suggest that activated monocytes and platelets may contribute to the raised levels of C–X–C chemokines in CHF. Damas et al. believe that the interaction between platelets and monocytes may be an important mediator of the systemic inflammatory response in CHF patients, and they suggest that IL-8 may be important participant in this process. Additionally, the ability of IL-8 to enhance free radical generation in both neutrophils and monocytes leads in turn to further production of C–X–C chemokines and increases the procoagulant activity in the syndrome of CHF [70].

2.15. Granulocyte-macrophage colony-stimulating factor (GM-CSF)
This glycoprotein is a member of the large family of hemopoietic cell colony-stimulating factors and regulates the proliferation and differentiation of myeloid progenitor cells [71]. This inflammatory factor in addition to its growth-promoting effects stimulates a range of functional activities of mature neutrophils, monocytes and eosinophils, including regulation of leukocyte adhesion, augmentation of surface antigen expression, superoxide anion generation and enhancement or induction of cytokine production [72]. GM-CSF, through the above mechanisms, may contribute to the pathophysiologic events involved in atherosclerosis and inflammation [73,74]. The biologic effects of GM-CSF on the immune system are summarized in Fig. 2. We have also demonstrated elevated GM-CSF levels in CHF, which are associated with the hemodynamic deterioration and neurohormonal activation characterizing this syndrome [75]. GM-CSF, a product of human monocyte–endothelial cell adhesive interaction, by virtue of its characteristics to modulate monocyte/macrophage function in vivo and subsequently to generate free radicals and enhance cytokine production may represent the common denominator of the pathophysiologic sequelae leading to abnormal nitric oxide-synthase expression in human myocardium and vascular endothelium of patients with CHF [75].


Figure 2
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  		Fig. 2 Biologic effects of GM-CSF on immune system.

 
2.16. Soluble intercellular adhesion molecule-1 (sICAM-1)
sICAM-1 is the soluble form of cellular adhesion molecule ICAM-1 which is a member of the immunoglobin gene superfamily found on the surface of macrophages and endothelial cells, and mediates the adhesion of inflammatory cells to endothelial wall of human vessels [76]. The soluble forms of ICAM-1 are parts which may be shed from the endothelial surface and have lower molecular weight than molecules expressed on endothelial cells, apparently due to absence of the cytoplasmic domain that remains in the cell of origin [77]. The induction or upregulation of ICAM-1, as well as the release of its soluble forms into circulation is a process common to inflammation in many tissues, including chronic inflammatory diseases, atherosclerosis and CHF [78–80]. Especially, sICAM-1 is an important cell adhesion signal that mediates leukocyte adhesion to the endothelium in blood under altered flow conditions such as CHF, and may reflect the abnormal inflammatory response and endothelial dysfunction characterizing this syndrome [80].

2.17. Soluble vascular cell adhesion molecule-1 (sVCAM-1)
sVCAM-1 is another well defined soluble adhesion molecule which participates actively to the inflammatory–endothelial adhesive interaction process in atherosclerotic disease and CHF [79,80]. sVCAM-1 and sICAM-1 have been used as non-invasive markers for the evaluation of endothelial dysfunction and its modification with various pharmacologic and non-pharmacologic interventions in patients with CHF [81,82].

2.18. Nuclear factor-{kappa}B (NF-{kappa}B)
The NF-{kappa}B system is a key player in control of transcription of genes for mediators of a variety of inflammatory responses in disorders such as atherogenesis and CHF [83,84]. Experimental studies have shown in CHF that the NF-{kappa}B family of proteins are present in endothelial cells and activated monocytes and regulate, through different protein complexes, the initiation or enhancement of transcription of various genes, including those influencing endothelial adhesion of leukocytes, the production of thrombogenic factors and the release of a variety of cytokines (e.g. TNF-{alpha}, IL-6) and chemokines (e.g. MCP-1) [85,86]. NF-{kappa}B is activated by a battery of stimuli leading to immune responses, including oxidative stress, TNF-{alpha} and angiotensin II [87,88]. Although the exact clinical significance of this nuclear factor in CHF is yet unclear, its role seems to be central to the goal of mapping the cellular and molecular pathways of vascular and myocardial injury as well as the subsequent cardiovascular remodeling in this syndrome [84–88]. Fig. 3 describes the biologic pathways of NF-{kappa}B activation, which are responsible for the cardiovascular injury in the syndrome of CHF.


Figure 3
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  		Fig. 3 Biologic stimuli and effects of NF-{kappa}B activation on cardiovascular system in CHF.

 

   3. Conclusions
Top
 Abstract
 1. Introduction
 2. Cytokine glossary
 3. Conclusions
References
 
Enhanced immune activation, reflected in increased circulating levels of various proinflammatory cytokines and other cytokine-related factors, has been recently recognized to play a significant role in the pathophysiology of CHF [4,9,11]. This review summarizes recent clinical and experimental evidence, which suggests that proinflammatory cytokines and other cytokine-related inflammatory factors are responsible for some aspects of the CHF phenotype contributing to the central (myocardial contractility and remodeling) and peripheral (skeletal muscular and endothelial function) abnormalities characterizing this syndrome. On the basis of the observed evidence for immune mechanisms of cardiovascular injury as an important pathogenic factor of CHF progression, the modulation of cytokine cascade may represent a new therapeutic paradigm for treating patients with CHF [89,90].


   References
Top
 Abstract
 1. Introduction
 2. Cytokine glossary
 3. Conclusions
 References
 

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