Journal Article

IL-10 targets IRF transcription factors to suppress IFN and inflammatory response genes by epigenetic mechanisms

Brauner, Caroline, Mishra, Bikash, Bachu, Mahesh, Ivashkiv, Lionel B., Yuan, Ruoxi, Wingert, Claire, Chaudhary, Vidyanath, Bell, Richard

2025

Overview

Interleukin-10 (IL-10) is pivotal in suppressing innate immune activation, in large part by suppressing induction of inflammatory genes. Despite decades of research, the molecular mechanisms underlying this inhibition have not been resolved. Here we utilized an integrated epigenomic analysis to investigate IL-10-mediated suppression of LPS and TNF responses in primary human monocytes. Instead of inhibiting core TLR4-activated pathways such as NF-κB, MAPK–AP-1 and TBK1–IRF3 signaling, IL-10 targeted IRF transcription factor activity and DNA binding, particularly IRF5 and an IRF1-mediated amplification loop. This resulted in suppression of inflammatory NF-κB target genes and near-complete suppression of interferon-stimulated genes. Mechanisms of gene inhibition included downregulation of chromatin accessibility, de novo enhancer formation and IRF1-associated H3K27ac activating histone marks. These results provide a mechanism by which IL-10 suppresses inflammatory NF-κB target genes, highlight the role of IRF1 in inflammatory gene expression and describe the suppression of IFN responses by epigenetic mechanisms. Ivashkiv and colleagues show that IL-10 inhibits the expression and DNA binding of IRF1 and IRF5, two transcription factors that have an amplifying role in the induction of inflammatory NF-κB target genes and directly induce the expression of ISGs.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/2502/2170 / 631/250/2504/342 / 631/250/262/2106/2108 / 631/250/38 / Activator protein 1 / Biomedical and Life Sciences / Biomedicine / Cells, Cultured / Chromatin / Deoxyribonucleic acid / DNA / Epigenesis, Genetic / Epigenetics / Gene expression / Gene Expression Regulation / Genes / Histones / Humans / Immune response / Immunity, Innate / Immunology / Infectious Diseases / Inflammation / Inflammation - genetics / Inflammation - immunology / Interferon / Interferon regulatory factor 1 / Interferon regulatory factor 3 / Interferon Regulatory Factor-1 - genetics / Interferon Regulatory Factor-1 - metabolism / Interferon Regulatory Factors - genetics / Interferon Regulatory Factors - metabolism / Interferons - genetics / Interferons - metabolism / Interleukin 10 / Interleukin-10 - immunology / Interleukin-10 - metabolism / Lipopolysaccharides - immunology / Lipopolysaccharides - pharmacology / MAP kinase / Molecular modelling / Monocytes / Monocytes - immunology / Monocytes - metabolism / NF-kappa B - metabolism / NF-κB protein / Signal Transduction / TLR4 protein / Toll-like receptors / Transcription factors