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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858669 | PMC |
| http://dx.doi.org/10.1038/srep25481 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors.
Nat Commun
December 2024
Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia.
Inflammasomes are defense complexes that utilize cytokines and immunogenic cell death (ICD) to stimulate the immune system against pathogens. Inspired by their dual action, we present cytokine-armed pyroptosis as a strategy for boosting immune response against diverse types of tumors. To induce pyroptosis, we utilize designed tightly regulated gasdermin D variants comprising different pore-forming capabilities and diverse modes of activation, representing a toolbox of ICD inducers.
View Article and Find Full Text PDFCLEC7A Knockdown Alleviates Ischemic Stroke by Inhibiting Pyroptosis and Microglia Activation.
J Integr Neurosci
December 2024
Department of Neurology, Hainan West Central Hospital, 571799 Danzhou, Hainan, China.
Background: Ischemic stroke (IS) is the leading cause of mortality worldwide. Herein, we aimed to identify novel biomarkers and explore the role of C-type lectin domain family 7 member A () in IS.
Methods: Differentially expressed genes (DEGs) were screened using the GSE106680, GSE97537, and GSE61616 datasets, and hub genes were identified through construction of protein-protein interaction networks.
Single Nucleotide Polymorphism of IL-18 (Rs 1946519) in Recurrent Aborted Iraqi Women and Its Association with Toxoplasmosis.
Iran J Parasitol
January 2024
Department of Biology, College of Science, Baghdad University, Baghdad, Iraq.
Background: We aimed to shed light on the risks of elevated levels of IL-18 in aborted women with toxoplasmosis by evaluating the risk or protective function of alleles or genotypes for single nucleotide polymorphism (SNP) of IL-18 (rs 1946519), which might be related to the susceptibility to toxoplasmosis.
Methods: IL-18 levels in patient and control blood samples were determined using ELISA, and the SNP IL-18 (ra 1946519) was subjected to the high-resolution method.
Results: Compared to healthy pregnant women (HP), the IL-18 serum levels of recurrent abortion with toxoplasmosis (RAWT), recurrent abortion without toxoplasmosis (RAWOT), and healthy non-pregnant (HNP) women decreased with significant differences.
Advances in research on the impact and mechanisms of pathogenic microorganism infections on pyroptosis.
Front Microbiol
December 2024
Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.
Pyroptosis, also known as inflammatory necrosis, is a form of programmed cell death characterized by the activation of gasdermin proteins, leading to the formation of pores in the cell membrane, continuous cell swelling, and eventual membrane rupture. This process results in the release of intracellular contents, including pro-inflammatory cytokines like IL-1β and IL-18, which subsequently trigger a robust inflammatory response. This process is a crucial component of the body's innate immune response and plays a significant role in combating infections.
View Article and Find Full Text PDFSystemic inflammatory regulators and age-related macular degeneration: a bidirectional Mendelian randomization study.
Front Genet
December 2024
Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, China.
Introduction: We investigated the relationship between systematic regulators of inflammation and the risk of age-related macular degeneration (AMD), both wet and dry forms, by using bidirectional, two-sample Mendelian randomization (MR).
Methods: We performed bidirectional two-sample Mendelian randomization analysis using genome-wide study (GWAS) data for 91 plasma proteins from 14,824 individuals of European descent across 11 study groups. Next, we utilized data from the FinnGen consortium to study AMD using the inverse- variance-weighted approach for Mendelian randomization.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!