Interleukin-18 signaling

IL18 also occurs as a short isoform, the result of an alternative splicing event that removes 57 bp/19 aa (IL18alpha). This short isoform has a modest synergistic action with the IL18 canonical active form.

The IL18 receptor (IL18R) belongs to the Interleukin-1 receptor/Toll like receptor superfamily. It consists of two subunits, Interleukin-18 receptor 1 (IL18R1, IL-18Rα, IL1Rrp1, IL18R1, IL-1R5) and Interleukin-18 receptor accessory protein (IL18RAP, IL18RB, IL-18Rβ,IL-18RacP, IL-18RII or IL-1R7). Both subunits have three extracellular immunoglobulin-like domains and one intracellular Toll/IL-1 receptor (TIR) domain. It is believed that IL18 binds first to IL18R1 and later recruits IL18RAP to form a high-affinity heterotrimeric complex. A short isoform of IL18R1 lacks the TIR domain (IL18R1 type II), which is required for signaling, leading to the suggestion that IL18R1 type II is a decoy receptor. A truncated form of IL18RAP containing only one of the three immunoglobulin domains stabilizes IL18 binding to IL18R1 but prevents signaling.

IL-18 binding protein (IL18BP), a 38-kDa soluble protein, is another negative regulator of IL18 signaling. It has some sequence homology with IL18R1. IL18BP binds with high affinity to mature IL18, preventing its interaction with IL18R1. Several isoforms IL18BP have been described. Interleukin-37 (IL37, IL-1F7), another negative regulator of IL18 signaling, is able to bind IL18BP and IL18RAP preventing signaling (Bufler et al.2002, Pan et al. 2001, Kumar et al. 2002).

IL18 stimulates Interferon gamma (IFNG, IFN-γ) production from T-helper lymphocytes cells (Th1) and macrophages and enhances the cytotoxicity of natural killer (NK) cells. IL18 stimulated IFNG production is synergistically amplified by other Th1-related cytokines such as IL2, IL15, IL12 and IL23.