Nature Immunology4, 920 - 927 (2003)
Published online: 17 August 2003; | doi:10.1038/ni968
SIGIRR, a negative regulator of Toll-like receptor−interleukin 1 receptor signaling
David Wald1, Jinzhong Qin1, Zhendong Zhao1, Youcun Qian1, Mayumi Naramura1, Liping Tian1, Jennifer Towne2, John E Sims2, George R Stark1
& Xiaoxia Li1
1
Cleveland Clinic Foundation, Department of Immunology, Cleveland, Ohio 44195, USA.
2
Amgen Corporation, 51 University Street, Seattle, Washington 98101, USA.
Correspondence should be addressed to Xiaoxia Li lix@ccf.org
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-B 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.
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B 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.
