Type I interferons protect from Toll-like receptor 9-associated liver injury and regulate IL-1 receptor antagonist in mice.
OBJECTIVE
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-1β-mediated 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.
Petrasek
Jan
J
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Dolganiuc
Angela
A
Csak
Timea
T
Kurt-Jones
Evelyn A
EA
Szabo
Gyongyi
G
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D006505:Hepatitis / Q000276:immunology* / Q000473:pathology*; D022781:Hepatocytes / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000235:genetics; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000276:immunology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology; D015854:Up-Regulation / Q000276:immunology
C508032:Ifnar1 protein, mouse; C507764:Il1rn protein, mouse; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C494235:Irf7 protein, mouse; C493486:Tlr2 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta