Abstract
Background Interleukin-16 (IL-16) is an important inflammatory regulator and has been shown to have a powerful effect on the regulation of the inflammatory response. Cardiac inflammation has been reported to be closely related to doxorubicin- (DOX-) induced cardiac injury. In this study, the role of IL-16 in DOX-induced cardiac injury and the possible mechanisms were examined. Methods Cardiac IL-16 levels were first measured in DOX- or saline-treated mice. Additionally, mice were pretreated with the anti-IL-16-neutralizing antibody (nAb) or isotype IgG for 1 day and further administered DOX or saline for 5 days. Then, cardiac injury, cardiac M1 macrophage levels, and cardiomyocyte apoptosis were analyzed. The effects of the anti-IL-16 nAb on macrophage differentiation and cardiomyocyte apoptosis were also investigated in vitro. Results DOX administration increased IL-16 expression in cardiac macrophages compared with that of saline treatment. The anti-IL-16 nAb significantly decreased serum levels of lactate dehydrogenase (LDH), myocardial-bound creatine kinase (CK-MB), and cardiac troponin T (cTnT) and elevated cardiac function in DOX-induced mice. Treatment with the anti-IL-16 nAb also reduced p65 pathway activation, decreased M1 macrophage-related marker and cytokine expression, and protected against cardiomyocyte apoptosis in DOX-induced mice. In cell studies, the anti-IL-16 nAb also reduced DOX-induced M1 macrophage differentiation and alleviated apoptosis in cardiomyocytes cocultured with macrophages. Conclusions The anti-IL-16 nAb protects against DOX-induced cardiac injury by reducing cardiac inflammation, and IL-16 may be a promising target to prevent DOX-related cardiac injury.
Highlights
As a drug that has been widely used in clinical chemotherapy, doxorubicin (DOX) has slowly been withdrawn as a frontline treatment due to severe cardiotoxicity and cardiac injury and further grave clinical consequences [1, 2]
The western blot results showed that DOX increased both cardiac IL-16 expression and serum IL-16 levels compared with the control condition (Figure 1(a))
We found that DOX administration significantly increased IL-16 release from cardiac macrophages
Summary
As a drug that has been widely used in clinical chemotherapy, doxorubicin (DOX) has slowly been withdrawn as a frontline treatment due to severe cardiotoxicity and cardiac injury and further grave clinical consequences [1, 2]. A variety of pathological injury factors, including inflammatory response, oxidative stress, excessive apoptosis, and energy metabolic failure, have been found to be involved in the progression of DOX-induced cardiotoxicity and cardiac injury [1,2,3,4]. Studies have shown that immune cell activation and the release of numerous inflammation-related substances play crucial roles in DOX-induced cardiotoxicity and cardiac injury [2,3,4]. Treatment with the anti-IL-16 nAb reduced p65 pathway activation, decreased M1 macrophage-related marker and cytokine expression, and protected against cardiomyocyte apoptosis in DOX-induced mice. The anti-IL-16 nAb reduced DOX-induced M1 macrophage differentiation and alleviated apoptosis in cardiomyocytes cocultured with macrophages. The anti-IL-16 nAb protects against DOXinduced cardiac injury by reducing cardiac inflammation, and IL-16 may be a promising target to prevent DOX-related cardiac injury
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