Synergistic Signaling of TLR and IFNα/β Facilitates Escape of IL-18 Expression from Endotoxin Tolerance

Abstract

<b>Rationale:</b> IL-18 is a member of the IL-1 cytokine family, and elevated blood IL-18 concentrations associate with disease activity in macrophage activation syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions.<b>Objectives:</b> Although recent investigations provide mechanistic evidence for a contribution of IL-18 to inflammation and hyperinflammation in sepsis and MAS, we sought to study regulatory mechanisms underlying human IL-18 expression.<b>Methods:</b> Samples from <i>in vivo</i> and <i>in vitro</i> endotoxin rechallenge experiments, patients with inflammatory disease, and isolated human monocytes treated with various stimulants and drugs were tested for cytokine gene and protein expression. Serum IL-18 expression with or without JAK/STAT inhibition was analyzed in two MAS mouse models and in a patient with recurrent MAS.<b>Measurements and Main Results:</b> Peripheral blood and monocytic IL-18 expression escaped LPS-induced immunoparalysis. LPS-stimulated primary human monocytes revealed specific IL-18 expression kinetics controlled by IFNα/β signaling. JAK/STAT inhibition or IFNβ neutralization during LPS stimulation blunted cytokine expression. Similarly, microtubule-destabilizing drugs abrogated LPS-induced <i>IL18</i> expression, but this effect could be fully reversed by addition of IFNα/β. <i>Ex vivo</i> analysis of inflammatory disease patients' whole blood revealed strong correlation of type I IFN score and <i>IL18</i> expression, whereas JAK/STAT inhibition strongly reduced IL-18 serum levels in two MAS mouse models and in a patient with recurrent MAS.<b>Conclusions:</b> Our data indicate that IL-18 (but not IL-1β) production from human monocytes requires cooperative Toll-like receptor and IFNα/β signaling. Interference with IFNα/β expression or signaling following JAK/STAT inhibition may control catastrophic hyperinflammation in MAS.