UNCONVENTIONAL INTERLEUKIN-1 SIGNALING IN CARDIAC DYSFUNCTION

ABSTRACT Interleukin-1β (IL-1β) is an apical pro-inflammatory cytokine that has also been shown to negatively modulate cardiac contractility. Whether IL-1β effects on systemic inflammation and cardiac function are intertwined and associated with each other, or whether they are independent of each other, is unknown. An unconventional signaling of the IL-1 receptor type I through the phosphoinositide-3 kinase γ (PI3K γ ), at least in part independent of the proinflammatory signaling, has been characterized in inflammation and cancer. We hypothesized that IL-1β would increase the expression of PI3K p110 γ in cardiomyocytes, which in turn results in selective induction of p87 co-signaling and cardiac dysfunction through a scaffolding function on phosphodiesterase 3B (PDE3B). Using genetically modified mice, we show that a kinase-independent PI3K p110 γ mechanism mediates IL-1-induced cardiac dysfunction. This may have compelling implications for the understanding and treatment of heart failure with reduced ejection fraction.