American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Mar 2020
Synergistic TLR/IFNα/β-Signaling Facilitates Escape of IL-18 Expression from Endotoxin Tolerance.
Rationale: 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. Objectives: 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. Methods: Samples from in vivo and in vitro 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. ⋯ Ex vivo analysis of inflammatory disease patients' whole blood revealed strong correlation of type I IFN score and IL18 expression, whereas JAK/STAT inhibition strongly reduced IL-18 serum levels in two MAS mouse models and in a patient with recurrent MAS. Conclusions: 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.