Interleukin 1 receptor signaling regulates DUBA expression and facilitates Toll-like receptor 9-driven antiinflammatory cytokine production.
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.
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Jose M
JM
González-Navajas
Jason
J
Law
Kim Phung
KP
Nguyen
Meha
M
Bhargava
Mary Patricia
MP
Corr
Nissi
N
Varki
Lars
L
Eckmann
Hal M
HM
Hoffman
Jongdae
J
Lee
Eyal
E
Raz
D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016264:Dextran Sulfate; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D034622:RNA Interference; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D017874:Immediate-Early Proteins; D007370:Interferon Type I; D009838:Oligodeoxyribonucleotides; D017472:Receptors, Interleukin-1; D048008:TNF Receptor-Associated Factor 3; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D016899:Interferon-beta; D016264:Dextran Sulfate; C433930:Dub2a protein, mouse; D010450:Endopeptidases