Toll-like receptors (TLRs) belong to the Toll-IL-1 receptor superfamily, which is defined by a common intracellular Toll-IL-1 receptor (TIR)-domain. These receptors employ related yet distinct signaling components and downstream pathways, leading to activation of the transcription factors NFkB, ATF and IRF3. Recent studies have also begun to unravel how these pathways are negatively regulated. SIGIRR (also known as TIR8), a member of Toll-IL-1R superfamily that does not activate the transcription factors NFkB, ATF and IRF3, instead negatively modulates responses. Inflammation is enhanced in SIGIRR-null mice as measured by enhanced chemokine induction after IL-1 injection and a reduced threshold for lethal endotoxin challenge. SIGIRR-deficient mice are more susceptible to DSS-induced inflammatory bowel disease. Cells from SIGIRR-null mice show enhanced activation in response to either IL-1 or certain Toll ligands. Therefore, SIGIRR functions as a biologically important modulator of Toll-IL-1R signaling.