UNCONVENTIONAL INTERLEUKIN-1 SIGNALING IN CARDIAC DYSFUNCTION

Toldo, S.; Narayan, P.; Mezzaroma, E.; Ghigo, A.; Damilano, F.; Marchetti, C.; Mauro, A. G.; Hirsch, E.; Van Tassell, B.; Abbate, A.

doi:10.1101/2025.03.09.642166

bioRxiv · 10.1101/2025.03.09.642166

UNCONVENTIONAL INTERLEUKIN-1 SIGNALING IN CARDIAC DYSFUNCTION

Toldo, S.·Narayan, P.·Mezzaroma, E.·Ghigo, A.·Damilano, F.·Marchetti, C.·Mauro, A. G.·Hirsch, E.·Van Tassell, B.·Abbate, A.

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Abstract

Interleukin-1{beta} (IL-1{beta}) is an apical pro-inflammatory cytokine that has also been shown to negatively modulate cardiac contractility. Whether IL-1{beta} 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{gamma} (PI3K{gamma}), at least in part independent of the proinflammatory signaling, has been characterized in inflammation and cancer. We hypothesized that IL-1{beta} would increase the expression of PI3K p110{gamma} 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{gamma} mechanism mediates IL-1-induced cardiac dysfunction. This may have compelling implications for the understanding and treatment of heart failure with reduced ejection fraction.

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Toldo, S., Narayan, P., Mezzaroma, E., Ghigo, A., Damilano, F., Marchetti, C., Mauro, A. G., Hirsch, E., Van Tassell, B., Abbate, A.. 2025-03-13. UNCONVENTIONAL INTERLEUKIN-1 SIGNALING IN CARDIAC DYSFUNCTION. https://doi.org/10.1101/2025.03.09.642166

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