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SIGIRR, a negative regulator of Toll-like receptor–interleukin 1 receptor signaling

Nature Immunology volume 4, pages 920–927 (2003)Cite this article

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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Figure 1: The expression of SIGIRR is cell- and tissue-specific and is down-regulated after immune challenge.
Figure 2: Overexpression of SIGIRR inhibits IL-1 and IL-18 signaling.
Figure 3: Targeted disruption of the mouse gene encoding SIGIRR.
Figure 4: SIGIRR-deficient mice show enhanced inflammatory responses to LPS and IL-1.
Figure 5: SIGIRR-deficient kidney cells show enhanced activation in response to LPS or IL-1.
Figure 6: Splenocytes from SIGIRR-deficient mice show enhanced activation in response to IL-1 or Toll ligands.
Figure 7: SIGIRR interacts with molecules involved in 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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Authors and Affiliations

  1. Department of Immunology, Cleveland Clinic Foundation, Cleveland, 44195, Ohio, USA

    David Wald, Jinzhong Qin, Zhendong Zhao, Youcun Qian, Mayumi Naramura, Liping Tian, George R Stark & Xiaoxia Li

  2. Amgen Corporation, 51 University Street, Seattle, 98101, Washington, USA

    Jennifer Towne & John E Sims

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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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