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The nuclear receptor LXR modulates interleukin-18 levels through multiple mechanisms

Pourcet, B; Gage, M C; Leon, T E; Waddington, K E; Pello, O M; Steffensen, K R; Castrillo, A; Valledor, A F; Pineda-Torra, I


B Pourcet

M C Gage

T E Leon

K E Waddington

O M Pello

K R Steffensen

A Castrillo

A F Valledor

I Pineda-Torra


IL-18 is a member of the IL-1 family involved in innate immunity and inflammation. Deregulated levels of IL-18 are involved in the pathogenesis of multiple disorders including inflammatory and metabolic diseases, yet relatively little is known regarding its regulation. Liver X receptors or LXRs are key modulators of macrophage cholesterol homeostasis and immune responses. Here we show that LXR ligands negatively regulate LPS-induced mRNA and protein expression of IL-18 in bone marrow-derived macrophages. Consistent with this being an LXR-mediated process, inhibition is abolished in the presence of a specific LXR antagonist and in LXR-deficient macrophages. Additionally, IL-18 processing of its precursor inactive form to its bioactive state is inhibited by LXR through negative regulation of both pro-caspase 1 expression and activation. Finally, LXR ligands further modulate IL-18 levels by inducing the expression of IL-18BP, a potent endogenous inhibitor of IL-18. This regulation occurs via the transcription factor IRF8, thus identifying IL-18BP as a novel LXR and IRF8 target gene. In conclusion, LXR activation inhibits IL-18 production through regulation of its transcription and maturation into an active pro-inflammatory cytokine. This novel regulation of IL-18 by LXR could be applied to modulate the severity of IL-18 driven metabolic and inflammatory disorders.


Pourcet, B., Gage, M. C., Leon, T. E., Waddington, K. E., Pello, O. M., Steffensen, K. R., …Pineda-Torra, I. (in press). The nuclear receptor LXR modulates interleukin-18 levels through multiple mechanisms.

Journal Article Type Article
Acceptance Date Apr 19, 2016
Deposit Date May 29, 2019
Publicly Available Date Aug 16, 2019
Journal Scientific Reports (Nature)
Peer Reviewed Peer Reviewed
Volume 6
Issue 6
Pages 25481
Public URL


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