Beneficial effects of IL-4 and IL-6 on rat neonatal target cardiac cells

Abstract

The nature of the early post-natal immune response in rodents appears to influence cardiac regeneration even though the underlying molecules remain poorly understood. Consistent with this idea, we show now significant changes in the expression of immune and cell movement gene pathways in heart samples from 1-and 7-day-old rats with ventricle resection. We then tested whether conditioned media from adult M2 anti-inflammatory macrophages target neonatal cardiac cells to a pro-regenerative like phenotype compared to the M1 pro-inflammatory macrophages. We found that M2 compared to M1 macrophage-conditioned media upregulates neonatal cardiomyocyte proliferation, suppresses myofibroblast-induced differentiation and stimulates endothelial cell tube formation. Using a cytokine array, we selected four candidate cytokine molecules uniquely expressed in M2 macrophage-conditioned media and showed that two of them (IL-4 and IL-6) induce endothelial cell proliferation whilst IL-4 promotes proliferation in neonatal cardiomyocytes and prevents myofibroblast-induced collagen type I secretion. Altogether, we provided evidence that adult M2 macrophage-conditioned media displays a paracrine beneficial pro-regenerative response in target cardiac cells and that IL-4 and IL-6 recapitulate, at least in part, these pleiotropic effects. Further characterization of macrophage immune phenotypes and their secreted molecules may give rise to novel therapeutic approaches for post-natal cardiac repair.

Urinary Trypsin Inhibitor Protects Tight Junctions of Septic Pulmonary Capillary Endothelial Cells by Regulating the Functions of Macrophages

“… 35 , 36 Our findings provide direct evidence of UTI protecting tight junction proteins in pulmonary capillary endothelial cells by regulating the function of macrophages. It is reported that a conditioned medium of M2 type macrophages can upregulate neonatal cardiomyocyte proliferation 37 and a conditioned medium of peritoneal macrophage from CO-treated rats stimulated endothelial cell proliferation. 38 Such evidence supports the view that macrophages can interfere with endothelial cells.…”

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

“…IL-4 signals via IL-4Rα/IL-13Rα1, a hybrid receptor used by both IL-4 and IL-13. It is noteworthy that the expression of this hybrid receptor is impaired in HF patients [69,70]. Although IL-4 does not suppress cardiac fibrosis, it enhances cardiac function by improving cardiac metabolic functions possibly through signaling via this hybrid receptor to promote M2 macrophage polarization and suppression of cardiac inflammatory response [67][68][69][70].…”

“…It is noteworthy that the expression of this hybrid receptor is impaired in HF patients [69,70]. Although IL-4 does not suppress cardiac fibrosis, it enhances cardiac function by improving cardiac metabolic functions possibly through signaling via this hybrid receptor to promote M2 macrophage polarization and suppression of cardiac inflammatory response [67][68][69][70]. Therefore, it is plausible that upregulation in IL-4 signaling in the sac/val treated ZO rats might have contributed to further improvements in DD compared to val alone.…”

β2-Adrenergic Receptors Increase Cardiac Fibroblast Proliferation Through the Gαs/ERK1/2-Dependent Secretion of Interleukin-6

“…Further, these studies did not identify a functional role of IL-6 generation. IL-6 is a pleiotropic cytokine that has many functions in the heart including regulation of cardiomyocyte hypertrophy and apoptosis and polarization of immune responses [ 57 , 73 , 74 , 75 ]. Additionally, there is abundant evidence for IL-6 influencing fibroblast functions including proliferation [ 76 ] and myofibroblast conversion [ 23 , 76 ].…”