IL-1 receptor (IL-1R) is a cytokine receptor which binds interleukin 1. Two main types of transmembrane receptors exist. The I IL-1 receptor (IL-1RI) is primarily responsible for transmitting the inflammatory effects of interleukin-1 (IL-1), while type Ⅱ IL-1 receptor (IL-1RⅡ) may act as a suppressor of IL-1 activity by competing for IL-1 binding. Also opposing the effects of IL-1 is the IL-1 receptor antagonist (IL-1Ra), a specific receptor antagonist.
Type I IL-1 receptor (IL-1RI) , the first known receptor of the TIR family, is the membrane receptor that binds the IL-1 ligands. Its extracellular part comprises three Ig domains which contain the ligand-binding area. The cytoplasmic portion, of about 213 amino acids in length, is homologous to the cytoplasmic domains of the other members of the TIR family. IL-1RI is responsible for the initiation of the signal-transduction mechanism that leads to cell proliferation activation.
In the binding process of IL-1RI and IL-1, the two N-terminal Ig domains of the receptor are in a quite rigid position because of an interdomain disulfide bond, whereas the third, membrane-proximal Ig domain is more flexibly connected to the other two. The receptor appears to wrap around the IL-1β molecule in such a way that IL-1 connects with the receptor in two places, a large area in the groove between the first and second domain, and a smaller area on the side of the third domain.
Binding of IL-1Ra to IL-1RI also occurs. IL-1Ra binds at the same site on IL-1RI as the main area of binding of IL-1β, that is, the groove between the first and second Ig domain. However, IL-1Ra fails to interact with the smaller area contacted by IL-1β in the third Ig domain. This leaves the structure of IL-1RI wrapping around IL-1Ra more extended and open as compared to that of the IL-1β-IL-1RI complex.
Type Ⅱ IL-1 receptor (IL-1RⅡ) is highly homologous to IL-1RI in the extracellular domain and can efficiently bind IL-1, but its cytoplasmic domain is very short, it does not contain a TIR domain, and is incapable of initiating signal transduction.
Type Ⅱ IL-1 receptor (IL-1RⅡ) can be cleaved from the cell surface through the action of a specific metalloproteinase, releasing a soluble form of IL-1RII (sIL-1RII). The membrane IL-1RII captures IL-1 on the cell surface, while sIL-1RII uptakes IL-1 in the microenvironment, and both divert it from binding to IL-1RI on the cell surface, thus inhibiting its biological activity. For this reason, IL-1RII has been dubbed ''decoy'' receptor. IL-1RII has a high affinity for IL-1β, but a much lower affinity for IL-1α and IL-1ra and it does not elicit a biologic response.
IL-1 receptor accessory protein (IL-1RAcP) shares approximately 25% amino acid identity to IL-1RI and IL- 1RII proteins. IL-1RAcP contains three Ig-like domains and a single transmembrane region. IL-1RAcP also has a long cytoplasmic domain homologous to the intracellular domain of IL-1RI, which has been implicated in signal transduction. Furthermore, IL-1RAcP is found in a complex with IL-1RI and the IL-1 agonists, but not with IL-1Ra.
Although, IL-1RAcP plays an essential and unique role in the biologic response to both IL-1α and IL-1β, it does not bind to either IL-1α or IL-1β. Once IL-1 has bound the IL-1RI chain, the IL-1RAcP is recruited to the ligand–receptor pair to form the high-affinity receptor complex. The approximation of the two intracellular domains of IL-1RI and IL-1RAcP consequent to the complex formation is the necessary and sufficient condition for initiation of signaling. IL-1RAcP is an essential signal transducing component of the functional IL-1R and should represent a novel target for blocking IL-1 function in human disease.
IL-1 family cytokines activate intracellular signaling pathways by binding to receptor subunits, such as IL-1 RI/IL-1 R1, IL-18 R alpha/IL-1 R5, IL-1 Rrp2/IL-1 R6, or ST2/IL-1 R4, which then recruits an accessory receptor to form the active receptor complex. Signaling cascades triggered by IL-1 alpha, IL-1 beta, IL-18, IL-33, IL-36 alpha, IL-36 beta, or IL-36 gamma activate MAPKs and NF-kappa B, leading to the expression of pro-inflammatory cytokines, chemokines, and secondary mediators of the inflammatory response.
In addition, several of these cytokines have been shown to regulate the differentiation and function of T helper cells. Other members of the IL-1 family inhibit inflammation by functioning as antagonists of IL-1 or IL-36 signaling. IL-1ra negatively regulates IL-1 signaling by binding to IL-1 RI and inhibiting its ability to interact with IL-1 alpha and IL-1 beta. Similarly, IL-36Ra binds to IL-1 Rrp2 and inhibits IL-36 signaling. Both IL-37/IL-1F7 and IL-1F10/IL-38 have also been suggested to have anti-inflammatory effects.
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