Proinflammatory Cytokines

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Overview of Proinflammatory Cytokines Involved in Heart Failure

The term cytokine is applied to a group of relatively small molecular weight protein molecules (generally 15-30 kDa) that are secreted by cells in response to a variety of different inducing stimuli. Classically, cytokines are thought to be secreted by neighboring "producer cells" to act in an autocrine, ajuxtacrine, or a paracrine fashion to influence the biological behavior of neighboring "target cells" (14,15). Although similar in many respects to polypeptide hormones, cytokines can be produced by a variety of different cell types in a number of different tissues, as opposed to being produced by a specific cell type in a specific organ, as is the case for polypeptide hormones. The group of cytokines that is responsible for initiating both the primary host response to a bacterial infection and the repair of tissue following tissue injury has been termed proinflammatory cytokines. Thus far two major classes of cytokines have been identified in heart failure: vasoconstrictor cytokines, such as endothelin, and vasodepressor proinflammatory cytokines, such as TNF, interleukin (IL)-6, IL-1 family (5). These inflammatory mediators are now known to be expressed by all nucleated cell types residing in the myocardium, including the cardiac myocyte, thus suggesting that these molecules may do more than simply orchestrate inflammatory responses in the heart (16). As discussed later, each of these cytokines is capable not only of influencing the expression of the other proinflammatory cytokines, but also of modulating cardiovascular performance when expressed at sufficiently high levels. Furthermore, peripheral circulating as well as intracardiac concentrations ofthese cytokines are elevated in patients with heart failure (1,9,17-20). Table 1 provides a summary of the studies that have examined circulating levels of cytokines and cytokine receptors in patients with heart failure. Most of these studies consistently described elevated levels of TNF-a in heart failure (1,8,9,17-31). The experimental and clinical data on the role of TNF-a, IL-6, and IL-1 in heart failure are reviewed in detail in the following sections. Comparatively less is known about IL-2 and interferon (IFN)-y in heart failure.

Tumor Necrosis Factor

For at least a century, proinflammatory cytokines have been known to be associated with sepsis and cardiogenic shock (32). At the beginning ofthe 20th century, a physician named William Coley, who began his career as a young surgeon at New York Memorial Hospital, found that a vaccine containing two killed bacteria, Streptococcus pyogenes and Serratia marcescens (later to become known as "Coley's toxins"), could induce tumor necrosis in unresectable malignancies but could also produce fatal hypotensive shock and pulmonary edema (33). "Coley's toxins," which caused tumor necrosis contained a "myocardial depressant factor," the molecular nature of which has eluded definitive identification in the intervening years. Subsequently, O'Malley et al. (34) showed that the tumor regression effects were mediated through the induction of a factor in the serum, which they named tumor-necrotizing factor, which was renamed by Lloyd J. Old's group as TNF (35). The sequence homology between TNF and lymphotoxin, a protein produced by lymphocytes that kills tumor cells, led to the renaming of TNF to TNF-a and lymphotoxin to TNF-P, respectively. Soon after, Beutler et al. (36) independently discovered mouse TNF-a as a factor that mediated wasting (cachexia) in mice. These two cytokines, TNF-a and TNF-P, laid the foundation for the isolation and identification of the larger family of cytokines, now known as the TNF superfamily referred to as TNF (37). Similarly, more than 25 yr ago, Lefer and Rovetto (38) reported that the sera of septic patients and experimental animals contained a "myocardial depressant factor." During the past decade, Parrillo and colleagues (39,40) using intact animals and in vitro isolated heart cell preparations to investigate systematically the factors that contributed to myocardial depression in systemic sepsis, concluded that it was in fact TNF and IL-1P that were responsible for most, if not all, of the reversible cardiac depression often seen with sepsis syndrome.

TNF, originally defined by its antitumor activity in vitro and in vivo in 1984 (35,41), is now recognized as a cytokine with pleiotropic biological capacities. Research during the past two decades has shown the existence of a superfamily of TNF proteins consisting of 19 members (including TNF-a) that signal through 29 receptors (37). These ligands, although regulating normal functions such as immune responses, hematopoiesis, and morphogenesis, have also been implicated in tumorigenesis, heart failure, transplant rejection, septic shock, viral replication, bone resorption, rheumatoid arthritis, and diabetes, hence indicating their role as "double-edged swords" (37). Blockers of TNF have been approved for human use in treating TNF-linked autoimmune diseases such as rheumatoid arthritis (37). Besides its cytostatic and cytotoxic effects on certain tumor cells, TNF influences growth, differentiation, and/or function of virtually every cell type investigated, including the cardiac myocyte (42,43). Moreover, TNF is thought to be part of an integral network that orchestrates inflammatory, immunological, and neurohormonal signaling. Thus, TNF stimulates macrophages and other cell types to produce other proinflammatory cytokines including IL-1, IL-6, IL-8, and TNF-a itself (14). The major cellular source of TNF is the activated macrophage, although a variety of different cell types, including lymphocytes, neutrophils, fibroblasts, endothelial cells, smooth muscle cells, and cardiac myocytes (5,9), are capable of producing this cytokine. In vivo, it appears that the expression of TNF is tissue specific. That is, under basal conditions, TNF is produced primarily by the thymus; however, after stimulation with lipopolysaccharide, TNF is also produced by the kidney, pancreas, uterus, and fallopian tubes, as well as the heart (44). In low concentrations ([10-10] mol/L), TNF-a is thought to act primarily as a paracrine or an autocrine regulator of leukocytes and endothelial cells and, therefore, regulates the inflammatory responses to microbes and facilitates tissue repair. In higher concentrations (©[10-8] mol/L), TNF-a production far exceeds the number of TNF receptors (TNFRs) in a given tissue, with the result that TNF-a "spills over" into the bloodstream, where it can act as an endocrine hormone and lead to metabolic wasting (cachexia), potentially lethal

Table 2

Deleterious Effects of Proinflammatory Cytokines in Heart Failurea

• Left ventricular dysfunction in humans (130)

• Pulmonary edema in humans (131)

• Cardiomyopathy in humans (132)

• Left ventricular remodeling experimentally (3,47,48)

• Abnormalities in myocardial metabolism experimentally (133)

• Anorexia and cachexia experimentally (134)

• P-Receptor uncoupling from adenylate cyclase experimentally (135)

• Abnormalities of mitochondrial energetics (136)

• Activation of fetal gene program experimentally (137)

• Cardiac myocyte apoptosis experimentally (56,138)

a Modified from ref. 7 with permission.

microvascular coagulation, and hypotension. Neither TNF mRNA nor TNF protein appears to be constitutively expressed in the nonfailing heart; by contrast, TNF mRNA and protein appear to be uniformly expressed in failing human hearts (9). Thus, similar to neurohormones, TNF and its family members are "double-edged swords." Whereas physiologically they are important cytokines and required for normal responses, their inappropriate expression is harmful (37).

Cytokines are thought to exert their effects by binding to specific receptors on the surface of the cell including the adult cardiac myocyte. In the case of TNF, this protein is known to bind to two types of TNFRs: TNFR1 (p 55) and TNFR2 (p 75) receptor. The adult human cardiac myocyte expresses both types of TNF receptors, and the type 1 receptor is responsible for mediating the negative inotropic effects of TNF (9,16). Studies have also shown that both TNFRs are proteolytically cleaved from the cell membrane, and that they exist in the circulation as circulating soluble receptors, referred to as sTNFRl and sTNFR2, respectively. Interestingly, both these receptors retain their ability to bind their ligand, as well as to inhibit the cytotoxic activities of TNF. It has been suggested that they may serve as "biological buffers" that are capable of rapidly neutralizing the highly cytotoxic activities of TNF (45).

Effects of TNF on heart. Many aspects of heart failure can be explained by the known biological effects of stress-activated proinflammatory cytokines. When expressed at sufficiently high concentration, TNF can mimic some aspects ofheart failure phenotype including but not limited to progressive LV dysfunction, pulmonary edema, LV remodeling, fetal gene expression, and cardiomyopathy (Table 2). The current literature suggests that TNF-a produces both an immediate and a delayed negative inotropic effect on myocardial contractility. Thus, the elaboration of cytokines may represent, much like neurohormones, a biological mechanism that is responsible for producing symptoms in patients with heart failure. As discussed subsequently, there is now a substantial body of evidence suggesting that the sustained expression of cytokines produces frank maladaptive effects in the heart, including deleterious effects on myocardial function and on LV remodeling.

Effect of TNF on LV Function. The effect of the proinflammatory cytokines on LV function was first reported in a series of important experimental studies showing that direct injections of TNF would produce hypotension, metabolic acidosis, hemoconcentration, and death within minutes, thus mimicking the hemodynamic response seen during endo-toxin-induced septic shock (46). Subsequent studies in dogs have shown that a single

Fig. 1. (A) Effect of continuous infusion of TNF-a on LV function in vivo. LV function was studied for 15 d in rats that underwent implantation of ip osmotic infusion containing either diluent (n = 20) or TNF-a (n = 38). After 15 d, osmotic infusion pumps were removed, and the animals were allowed to recover for an additional 15 d. LV fractional shortening was reduced with TNF-a infusion and improved after infusion pumps (3). (B) Effect of continuous TNF-a infusion in rats on LV geometry in vivo. LV dimensions were studied for 15 d following implantation of an ip osmotic infusion containing either diluent (n = 20) or TNF-a (2.5 ^g/[kg. min]; n = 38). LV dimensions increased with TNF-a infusion, indicative of LV remodeling induced by TNF-a (3). (C) M-mode echocardiography images of rat heart at baseline and at15 d of TNF-a infusion showing reduction in LV fractional shortening and increase in LV dimensions (3). *Statistical significance withp < 0.05. LVEDD, left-ventricular end diastolic diameter; LVESD, left-ventricular end systolic diameter. (Reproduced from ref. 3 with permission of the American Heart Association ©1998.)

Fig. 1. (A) Effect of continuous infusion of TNF-a on LV function in vivo. LV function was studied for 15 d in rats that underwent implantation of ip osmotic infusion containing either diluent (n = 20) or TNF-a (n = 38). After 15 d, osmotic infusion pumps were removed, and the animals were allowed to recover for an additional 15 d. LV fractional shortening was reduced with TNF-a infusion and improved after infusion pumps (3). (B) Effect of continuous TNF-a infusion in rats on LV geometry in vivo. LV dimensions were studied for 15 d following implantation of an ip osmotic infusion containing either diluent (n = 20) or TNF-a (2.5 ^g/[kg. min]; n = 38). LV dimensions increased with TNF-a infusion, indicative of LV remodeling induced by TNF-a (3). (C) M-mode echocardiography images of rat heart at baseline and at15 d of TNF-a infusion showing reduction in LV fractional shortening and increase in LV dimensions (3). *Statistical significance withp < 0.05. LVEDD, left-ventricular end diastolic diameter; LVESD, left-ventricular end systolic diameter. (Reproduced from ref. 3 with permission of the American Heart Association ©1998.)

infusion of TNF results in abnormalities of systolic function within the first 24 h of infusion (47). Similarly, experimental studies in rats have shown that circulating concentrations of TNF that are observed in patients with heart failure are sufficient to produce persistent negative inotropic effects that are detectable at the level of the cardiac myocyte; moreover, the negative inotropic effects of TNF are completely reversible when the TNF infusion is stopped (3) (Fig. 1A,C). In subsequent studies in transgenic mice with targeted overexpression ofTNF in the cardiac compartment, forced overexpression of TNF resulted in depressed LV ejection performance; notably, depressed LV ejection performance was dependent on TNF "gene dosage" (48,49).

Similar to TNF-a, both IL-1 and IL-6 produce negative inotropic effects in various experimental models (50,51). In addition to TNF-a and IL-6, other cytokines directly implicated in mediating myocardial depression in systemic sepsis and other forms of cardiac dysfunction include IL-1p, IL-2, and IFN-y (52).

Effect of TNF on LV remodeling. In experimental studies, overexpression of TNF can result in LV remodeling (3,48). Specifically, in a rat model, we demonstrated that TNF-a infusion induced a time-dependent increase in LV end diastolic dimension (3). In this

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