IL-1R8 inhibits IL-1R1, IL-18 and IL-33 signaling by competing with MyD88 and IRAK recruitment at the TIR domain, thus dampening the signaling pathway leading to NF-kB activation. In addition, in T and epithelial cells, IL-1R8 inhibits IL-1-dependent activation of the mTOR pathway and of MAPK, thus controlling cell proliferation and survival. IL-1R8 is also a co-receptor of IL-18Rα for IL-37, necessary for the activation of an anti-inflammatory signaling pathway that involves inhibition of MAPKs, NF-κB and TAK1, the pseudo-starvational effects on the mTOR pathway, and the activation of STAT3, Mer, PTEN and p62. IL-1R8 also inhibits the activation of TLR-dependent signaling pathways leading to MAPK and NF-kB activation.