Abstract
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-κB 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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Acknowledgements
This work was supported by the National Institutes of Health (grant GM 600020 to X.L.) and by Amgen.
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Wald, D., Qin, J., Zhao, Z. et al. SIGIRR, a negative regulator of Toll-like receptor–interleukin 1 receptor signaling. Nat Immunol 4, 920–927 (2003). https://doi.org/10.1038/ni968
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DOI: https://doi.org/10.1038/ni968
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