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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.
Highlights
Interleukin (IL)-18 and IL-1β are highly potent inflammatory cytokines that belong to the Interleukin-1 family of immunomodulators, and are implicated in a range of severe and diverse autoimmune and inflammatory diseases as well as metabolic and vascular disorders including rheumatoid arthritis, diabetes atherosclerosis[1]
IL-18 is a potent pro-inflammatory molecule implicated in a number of inflammatory and autoimmune diseases including rheumatoid arthritis, multiple sclerosis and psoriasis as well as inflammatory and metabolic diseases including atherosclerosis[1,39]
IL-18 is a member of the IL-1 family of central mediators of innate immunity and inflammation and its tight regulation via receptor antagonists, decoy receptors and signaling inhibitors is needed to ensure the right balance between amplification of innate immunity and uncontrolled inflammation[1]
Summary
Interleukin (IL)-18 and IL-1β are highly potent inflammatory cytokines that belong to the Interleukin-1 family of immunomodulators, and are implicated in a range of severe and diverse autoimmune and inflammatory diseases as well as metabolic and vascular disorders including rheumatoid arthritis, diabetes atherosclerosis[1]. LXR transcriptional activity is induced by certain oxysterols and synthetic compounds including T090131720 or GW396521 Both LXR isoforms, LXRα and LXRβ , control macrophage cholesterol homeostasis and regulate macrophage inflammatory responses, phagocytosis and apoptosis[22,23]. LXRs inhibit the transcription of pro-inflammatory genes (including IL-6, IL-1β and iNOS) lacking LXREs in their promoters or enhancers. They do so by antagonising the activity of transcription factors such as NF-κ B or AP1 without directly binding to DNA themselves, in a process termed transrepression[23]. We show for the first time that LXRs inhibit IL-18 gene expression and negatively regulate caspase 1 levels (and IL-18 processing and activation by the inflammasome). LXRs exert multiple actions on IL-18 and IL-1β regulation
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