Macrophage migration inhibitory factor is a cardiac-derived myocardial depressant factor

Abstract

Macrophage migration inhibitory factor (MIF) is a pluripotent proinflammatory cytokine that is ubiquitously expressed in organs, including the heart. However, no specific role for MIF in modulating cardiac performance has yet been described. Therefore, we examined cardiac MIF expression in mice after LPS challenge (4 mg/kg) and tested the hypothesis that MIF is a mediator of LPS-induced cardiac dysfunction. Western blots of whole heart lysates, as well as immunohistochemistry, documented constitutive MIF protein expression in the heart. Cardiac MIF protein levels significantly decreased after LPS challenge, reaching a nadir at 12 h, and then returned to baseline by 24 h. This pattern was consistent with MIF release from cytoplasmic stores after endotoxin challenge. After release of protein, MIF mRNA levels increased 24–48 h postchallenge. To determine the functional consequences of MIF release, we treated LPS-challenged mice with anti-MIF neutralizing antibodies or isotype control antibodies. Anti-MIF-treated animals had significantly improved cardiac function, as evidenced by a significant improvement in left ventricular (LV) fractional shortening percentage at 8, 12, 24, and 48 h after endotoxin challenge. In support of these findings, perfusion of isolated beating mouse hearts (Langendorff preparation) with recombinant MIF (20 ng/ml) led to a significant decrease in both systolic and diastolic performance [LV pressure (LVP), positive and negative first derivative of LVP with respect to time, and rate of LVP rise at developed pressure of 40 mmHg]. This study demonstrates that MIF mediates LPS-induced cardiac dysfunction and suggests that MIF should be considered a pharmacological target for the treatment of cardiac dysfunction in sepsis and potentially other cardiac diseases.

C5a-Blockade Improves Burn-Induced Cardiac Dysfunction

“…Proinflammatory cytokines (such as TNF-␣, IL-1␤, and IL-6) have been described as cardiodepressive agents (21)(22)(23). Reactive oxygen intermediates and macrophage migration inhibitory factor (MIF) have been shown to exert cardiodepressive effects following thermal injury (24). To date, the potential role of complement activation products in the setting of cardiac dysfunction following burn injury has not been investigated.…”

Molecular Events in the Cardiomyopathy of Sepsis

“…Levels of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and the complement anaphylatoxin, C5a, are known to be elevated in the circulation during sepsis and have been found to directly depress myocardial contractility in vitro (34)(35)(36). It is noteworthy that cardiomyocytes are able to generate TNF-α, IL-1β, IL-6, cytokine-induced neutrophil chemoattractant (CINC)-1, macrophage migration inhibitory factor (MIF), and high-mobility group box (HMGB)-1 during endotoxemia, sepsis, and burn injury (37)(38)(39). This is a seemingly paradoxical phenomenon because such cardiomyocyte products would impair cardiomyocyte performance ( Figure 1).…”

Macrophage Migration Inhibitory Factor in Pediatric Patients Undergoing Surgery for Congenital Heart Repair

“…The source of circulating MIF in this surgical setting is not known, although activation of the hypothalamicpituitary-adrenal axis has been suggested (28,29). MIF is also produced by numerous tissues including the myocardium and secreted from circulating macrophages and neutrophils (8,11,30). MIF has been shown to cause myocardial contractile depression, and inactivation of MIF by chemical inhibitors or neutralizing antibodies have improved cardiac function in experimental animal models of sepsis (8,16,17).…”

“…Similar to other cytokines, MIF is present in the myocardium (8) and has been shown to be secreted in response to oxidative stress as would occur during myocardial infarction or with ischemia/ reperfusion injury of the heart during CPB (9,10). In adult patients experiencing acute myocardial infarction, serum MIF levels were shown to be significantly elevated within the first 30 h (11).…”

“…Several studies of adult patients undergoing surgery with cardiopulmonary bypass have reported elevated circulating levels of MIF immediately after surgery that were associated with mild pulmonary dysfunction and multiple organ dysfunction (12)(13)(14). Garner et al (8) reported that in animal models of sepsis, cardiac-derived MIF could act as a myocardial depressant factor, and that perfusion of the isolated heart with recombinant MIF led to decreased systolic and diastolic function. In our studies of polymicrobial sepsis in rats, elevated levels of circulating MIF were associated with a significant impairment in cardiac contractile function, and this effect could be attenuated by inhibition of MIF activity Macrophage migration inhibitory factor (MIF), a proinflammatory mediator, has been shown to be elevated following heart surgery in adults and may be associated with several postoperative complications, including cardiac and pulmonary dysfunction.…”