Type i interferons protect from toll-like receptor 9associated liver injury and regulate IL-1 receptor antagonist in mice

Jan Petrasek, Angela Dolganiuc, Timea Csak, Evelyn A. Kurtjones, Gyongyi Szabo

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Background & Aims Liver inflammation and injury are mediated by the innate immune response, which is regulated by Toll-like receptors (TLR). Activation of TLR9 induces type I interferons (IFNs) via the interferon regulatory factor (IRF)-7. We investigated the roles of type I IFNs in TLR9-associated liver injury. Methods Wild-type (WT), IRF7-deficient, and IFN-α/β receptor 1 (IFNAR1)-deficient mice were stimulated with TLR9 or TLR2 ligands. Findings from mice were verified in cultured hepatocytes and liver mononuclear cells (LMNCs) as well as in vivo experiments using recombinant type I IFN and interleukin-1 receptor antagonist (IL-1ra). Results Type I IFNs were up-regulated during TLR9-associated liver injury in WT mice. IRF7- and IFNAR1-deficient mice, which have disruptions in type I IFN production or signaling, respectively, had increased liver damage and inflammation, decreased recruitment of dendritic cells, and increased production of tumor necrosis factor α by LMNCs. These findings indicate that type I IFNs have anti-inflammatory activities in liver. IL-1ra, which is produced by LMNCs and hepatocytes, is an IFN-regulated antagonist of the proinflammatory cytokine IL-1β; IRF7- and IFNAR1-deficient mice had decreased levels of IL-1ra compared with WT mice. IL-1ra protected cultured hepatocytes from IL-1βmediated sensitization to cytotoxicity from tumor necrosis factor α. In vivo exposure to type I IFN, which induced IL-1ra, or administration of IL-1ra reduced TLR9-associated liver injury; the protective effect of type I IFNs therefore appears to be mediated by IFN-dependent induction of IL-1ra. Conclusions Type I IFNs have anti-inflammatory effects mediated by endogenous IL-1ra, which regulates the extent of TLR9-induced liver damage. Type I IFN signaling is therefore required for protection from immune-mediated liver injury.

Original languageEnglish
Pages (from-to)697-708.e4
JournalGastroenterology
Volume140
Issue number2
DOIs
Publication statusPublished - Feb 2011

Keywords

  • Bacterial DNA
  • Immunology
  • Innate Immunity
  • Liver Disease

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Fingerprint Dive into the research topics of 'Type i interferons protect from toll-like receptor 9associated liver injury and regulate IL-1 receptor antagonist in mice'. Together they form a unique fingerprint.

  • Cite this