SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling.
The Toll-like receptor-interleukin 1 receptor signaling (TLR-IL-1R) receptor superfamily is important in differentially recognizing pathogen products and eliciting appropriate immune responses. These receptors alter gene expression, mainly through the activation of nuclear factor-kappaB and activating protein 1. SIGIRR (single immunoglobulin IL-1R-related molecule), a member of this family that does not activate these factors, instead negatively modulates immune responses. Inflammation is enhanced in SIGIRR-deficient mice, as shown by their enhanced chemokine induction after IL-1 injection and reduced threshold for lethal endotoxin challenge. Cells from SIGIRR-deficient mice showed enhanced activation in response to either IL-1 or certain Toll ligands. Finally, biochemical analysis indicated that SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way. Our data show that SIGIRR functions as a biologically important modulator of TLR-IL-1R signaling.
Wald
David
D
Cleveland Clinic Foundation, Department of Immunology, Cleveland, Ohio 44195, USA.
Qin
Jinzhong
J
Zhao
Zhendong
Z
Qian
Youcun
Y
Naramura
Mayumi
M
Tian
Liping
L
Towne
Jennifer
J
Sims
John E
JE
Stark
George R
GR
Li
Xiaoxia
X
D000818:Animals; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D007375:Interleukin-1 / Q000276:immunology; D020382:Interleukin-18 / Q000276:immunology; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1 / Q000276:immunology
D018925:Chemokines; D007375:Interleukin-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1; D012313:RNA