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Department of Cardiothoracic Surgery, Erasmus MC Rotterdam, Dr Molewaterplein 50, Rotterdam 3015 GE, the Netherlands
(Email: npvdkaaij{at}gmail.com; a.j.j.c.bogers{at}erasmusmc.nl).
The present study by Cha and colleagues [1] was performed to establish that toll-like receptor 4 (TLR4) exerts its influence on post-ischemic myocardial function through tumor necrosis factor-alpha (TNF-
) and interleukin (IL)-1β production. The authors state in the introduction that the effect of TLR4 signaling on cardiac function and the contribution of TLR4 to the production of TNF- and IL-1β remain to be determined. They also proclaim that the influence of TNF- and IL-1β on cardiac function is unclear. Unfortunately, however, scrutinizing the available literature results in useful additional data providing a more sound rationale for this study. First of all, although the authors are technically correct in the fact that it is not totally clear whether TLR4 plays a role in cardiac dysfunction after ischemia and reperfusion (IR), it has been shown several times before that myocardial infarct size is reduced after TLR4 blockade [2–4]. Since infarct size and cardiac function are closely related, the finding that cardiac dysfunction following myocardial infarction is reduced in TLR4 defective mice is not very unexpected. Second, several studies have suggested a link between TLR4 signaling and pro-inflammatory cytokine production [2, 4–6]. In this regard, Shimamoto and colleagues [2] showed that treatment with a specific TLR4 antagonist before the induction of myocardial ischemia resulted in less jun N-terminal kinase (JNK) phosphorylation, less nuclear factor kappa beta (NF-
β) translocation, and decreased levels of cytokine expression (eg, TNF-, IL-1β, macrophage inflammatory protein (MIP)-1a, MIP-2, monocyte chemoattractant protein 1 (MCP-1), and IL-6). Comparable results were found in a model of lung IR injury in TLR4 defective mice [5] and in a heart transplantation model with the induction of clinical relevant cold ischemia [6]. Finally, the finding that TNF- and IL-1β production contribute to cardiac dysfunction after myocardial IR is supported by many other articles, although low levels of TNF- may have a beneficial effect on IR injury.
Nevertheless, the study by Cha and colleagues [1] still contains interesting elements, such as the excellent experimental design. To prove their hypothesis, the authors have used a subtraction from Koch's postulates. In this view, they have first demonstrated that TNF- and IL-1β levels are elevated in wild type mice with the disease (ie, impaired cardiac dysfunction after myocardial IR injury). Next, it is illustrated that less cardiac dysfunction is found in TLR4 defective and TNF- and IL-1β knockout mice, suggesting a causal relationship between these factors and the disease. However, the confirmed lower levels of TNF- and IL-1β in TLR4 defective mice do suggest (but do not prove) that TLR4 causes cardiac dysfunction through TNF- and IL-1β. Convincing evidence is provided by the administration of TNF- and IL-1β to TLR4 defective mice, which resulted in comparable levels of injury as found in wild type controls.
In conclusion, this study could have been better documented, but is very well executed, and most importantly it provides strong evidence that TLR4 causes impairment of post-ischemic myocardial function through TNF- and IL-1β production.
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