Interleukin-10 exhibit dose-dependent effects on macrophage phenotypes and cardiac remodeling after myocardial infarction
Jing J. Zhang, Rodrigue Rizk, Xiaoping Li, Brandon G. Lee, Mason L. Matthies, Kennedy A. Bietz, Kang Kim, Johnny Huard, Yadong Wang, William C. W. Chen
Abstract
Introduction Interleukin-10 (IL-10) is a potent immunomodulatory cytokine widely explored as a therapeutic agent for diseases, including myocardial infarction (MI). High-dose IL-10 treatment may not achieve expected outcomes, raising the question of whether IL-10 has dose-dependency, or even uncharted side-effects from overdosing. We hypothesized that IL-10 has dose-dependent effects on macrophage (Mφ) phenotypic transition and cardiac remodeling after MI. Methods Using RAW264.7 monocyte models, we examined whether administering differential doses of exogenous IL-10 (0–1,000 ng/mL) perturbs classic M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes of polarized Mφ or even alters the phenotypic transition of prospective M1 and M2 polarization. We then investigated the impact of single intramyocardial IL-10 administration on cardiac function, structure, and inflammation post-MI, using a mouse MI model. Results Compared with 0-ng/mL control, 250-ng/mL IL-10 had the strongest overall effects in decreasing M1 and increasing M2 phenotypes on polarized Mφ while ≥500-ng/mL IL-10 dampened M1 polarization and augmented native IL-10 secretion more effectively than low doses in vitro . Echocardiography revealed that the 250-ng group had consistently higher contractile function and lower left ventricular (LV) dilatation than the saline control over 6 weeks while ≥1,000-ng groups exhibited transient lower LV ejection fraction at 5 days post-MI in vivo . Moreover, different doses of IL-10 differentially modulated myocardial gene expression, phagocytic cell infiltration at the infarct, LV fibrosis, and revascularization post-MI, with some, but not all, doses exerting beneficial effects. Discussion Our study suggested that IL-10 has an effective dose range on Mφ phenotypes, and intramyocardial IL-10 treatment may trigger cardioprotective or unwanted effects post-MI in a dose-dependent manner.