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

Abstract

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.

Citation

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. (in press). The nuclear receptor LXR modulates interleukin-18 levels through multiple mechanisms. https://doi.org/10.1038/srep25481

• 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
• DOI: https://doi.org/10.1038/srep25481
• Public URL: https://rvc-repository.worktribe.com/output/1396974