IL1RAP

Greenfeder et al. 1995

The accessory protein of the interleukin-1 receptor (IL-1RAcP) belongs to the proteins of the immunoglobulin superfamily and consists of soluble and membranous isoforms. IL-1RAcP plays an essential role in the signaling of cytokines of the interleukin-1 family such as interleukin-1, interleukin-33 and interleukin-36 as well as the tyrosine kinases FLT3 and C-Kit.

IL-1RAcP generally initiates the inflammatory signaling pathway by recruiting signaling mediators, including MYD88 and IRAK. Chronic inflammation following sustained cytokine receptor signaling is a critical process in the pathogenesis of many inflammatory diseases, including autoimmunity, obesity, psoriasis, type 1 diabetes, endometriosis, preeclampsia, and Alzheimer's disease. Recently, abnormal IL-1RAcP signaling has been attributed a central role in the development of these chronic inflammatory diseases. Targeting the IL-1RAcP signaling pathway also suggests its potential as a therapeutic target for inflammatory and autoimmune diseases.

IL-1RAcP belongs to the superfamily of immunoglobulin (Ig) proteins and consists of three extracellular Ig domains and a cytoplasmic domain called Toll/IL-1 receptor (TIR). IL-1RAcP plays a crucial role in interleukin-1 receptor I signaling. Its internalization is necessary for the initiation of the signaling process. In addition, however, a number of other molecules are required for this process, including the interleukin-1 receptor, IL-1RAcP and interleukin-1 (alpha or beta). This is the only way to complete the initiation of the signaling cascade. When interleukin-1, interleukin-33 and interleukin-36 bind to their receptors, these processes can lead to the aggregation of IL-1RAcP and the recruitment of the adaptor protein MyD88.

Interleukin-1 receptor-associated kinase (IRAK) is another protein involved in this signaling. The interaction of IRAK with TRAF6 promotes further activation of the transcription factors nuclear factor kappa B (NF-κB) and the N-terminal region of Janus kinase (JAK).

To date, four isoforms of IL-1RAcP have been identified. The membranous form, mIL-1RAcP, plays an influential role in receptor-mediated signaling of IL-1, IL-33, IL-36 as well as FLT3 and C-Kit in AML cells. The role of C-Kit and FLT3 in tumor growth and progression, including angiogenesis, cell proliferation and cell migration, SCF (C-Kit ligand) and FLT3 ligand bind to c-Kit and FLT3, respectively, causing homodimerization and autophosphorylation of the receptors and activation of various signaling pathways. Janus kinase (JAK) interacts with phosphorylated FLT-3 and c-Kit and activates various STAT molecules as transcription factors. Activation of PI3 kinase, Src and the small G protein Ras activates a variety of signaling pathways, including MAP kinase and Akt/PKB.

1. Arend WP et al. (2008) IL-1, IL-18, and IL-33 families of cytokines. Immunol Rev 223:20-38.
2. Zarezadeh Mehrabadi A et al. (2024) Interleukin-1 receptor accessory protein (IL-1RAP): A magic bullet candidate for immunotherapy of human malignancies. Crit Rev Oncol Hematol. 193:104200.
3. Zarezadeh Mehrabadi A et al. (2022) The roles of interleukin-1 receptor accessory protein in certain inflammatory conditions. Immunology 166:38-46.