Abstract
The interleukin 1 receptor (IL-1R) and the Toll-like receptors (TLRs) are highly homologous innate immune receptors that provide the first line of defense against infection. We show that IL-1R type I (IL-1RI) is essential for TLR9-dependent activation of tumor necrosis factor receptor-associated factor 3 (TRAF3) and for production of the antiinflammatory cytokines IL-10 and type I interferon (IFN). Noncanonical K63-linked ubiquitination of TRAF3, which is essential for type I IFN and IL-10 production, was impaired in Il1r1(-/-) CD11c(+) dendritic cells. In contrast, degradative ubiquitination of TRAF3 was not affected in the absence of IL-1R1 signaling. Deubiquitinating enzyme A (DUBA), which selectively cleaves K63-linked ubiquitin chains from TRAF3, was up-regulated in the absence of IL-1R1 signaling. DUBA short interference RNA augmented the TLR9-dependent type I IFN response. Mice deficient in IL-1RI signaling showed reduced expression of IL-10 and type I IFN and increased susceptibility to dextran sulphate sodium-induced colitis and failed to mount a protective type I IFN response after TLR9 ligand (CpG) administration. Our data identifies a new molecular pathway by which IL-1 signaling attenuates TLR9-mediated proinflammatory responses.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cells, Cultured
-
Colitis / chemically induced
-
Colitis / genetics
-
Colitis / metabolism
-
Cytokines / metabolism*
-
Dendritic Cells / cytology
-
Dendritic Cells / drug effects
-
Dendritic Cells / metabolism
-
Dextran Sulfate
-
Endopeptidases / genetics
-
Endopeptidases / metabolism*
-
Female
-
Immediate-Early Proteins / genetics
-
Immediate-Early Proteins / metabolism*
-
Immunoblotting
-
Interferon Type I / genetics
-
Interferon Type I / metabolism
-
Interferon-beta / metabolism
-
Interleukin-10 / metabolism
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Oligodeoxyribonucleotides / pharmacology
-
RNA Interference
-
Receptors, Interleukin-1 / deficiency
-
Receptors, Interleukin-1 / genetics
-
Receptors, Interleukin-1 / physiology*
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction
-
TNF Receptor-Associated Factor 3 / genetics
-
TNF Receptor-Associated Factor 3 / metabolism
-
Toll-Like Receptor 9 / genetics
-
Toll-Like Receptor 9 / metabolism*
Substances
-
Cytokines
-
Immediate-Early Proteins
-
Interferon Type I
-
Oligodeoxyribonucleotides
-
Receptors, Interleukin-1
-
TNF Receptor-Associated Factor 3
-
Toll-Like Receptor 9
-
Interleukin-10
-
Interferon-beta
-
Dextran Sulfate
-
Dub2a protein, mouse
-
Endopeptidases