IL-1 Receptor Accessory Protein (also IL-1 R3) is a ubiquitous 70-90 kDa member of the interleukin-1 receptor family of proteins (1-5). It serves as a non-ligand-binding accessory component of the receptors for IL-1 alpha, IL-1 beta, and IL-33 (6, 7). Together with IRAK4 and MyD88, it generates a functional signaling complex with IL-1 RI; by itself, it generates a non-signaling, but high-affinity binding complex with IL-1 RII (8). In addition, it interacts with ST2 on mast cells and Th2 T cells to create a functional IL-33 receptor complex (7). Mature human IL-1 RAcP is a type I transmembrane glycoprotein that is 550 amino acids in length. It contains a 347 amino acid (aa) extracellular region (aa 21-367), a 21 aa transmembrane segment, and a 182 aa cytoplasmic domain (9). The extracellular region shows three C2-type Ig-like domains, the most membrane proximal of which is suggested to be responsible for dimerization with IL-1 RI (10). There are three alternative splice forms reported for IL-1 RAcP. One is transmembrane and shows a 239 aa substitution for the C-terminal 122 amino acids (11). The other two are soluble; one shows a six aa substitution for aa 351-570, while a second shows a 45 aa substitution for aa 302-579 (12, 13). The soluble receptor isoforms appear to be inhibitory to IL-1 signaling. When present with soluble IL-1 RII, soluble IL-1 RAcP increases the IL-1 binding affinity of IL-1 RII more than 100-fold, thus neutralizing the effects of IL-1 (14). The human and mouse IL-1 RAcP precursors are 89% aa identical; within the extracellular region, they share 86% aa identity.