Interleukin-18 (IL18, pro-IL18) is a pleiotropic and pro inflammatory cytokine. It belongs to the Interleukin-1 (IL1 superfamily (Alboni et al. 2010, Krumm et al. 2017, Dinarello 1999). IL18 is synthesized as an inactive 24-kDa precursor protein that is cleaved by extracellular proteases such as caspase-1, protease 3, serine protease, elastase or cathepsin G (Fantuzzi & Dinarello 1999, Gracie et al. 2004, Sugawara et al. 2001), forming an 18-kDa mature protein (Arend et al. 2008, Akita et al. 1997, Fantuzzi et al. 1998, Ghayur et al. 1997, Gu et al. 1997, Ushio et al. 1996).
IL18 also occurs as a short isoform, the result of an alternative splicing event that removes 57 bp/19 aa (IL18alpha) (Conti et al. 1997, Yang et al. 2005). 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 (O'Neill & Dinarello 2000, Sims 2002). It is believed that IL18 binds first to IL18R1 and later recruits IL18RAP to form a high-affinity heterotrimeric complex (Sims 2002, Sergi & Pentilla 2004, Alboni et al. 2009). A short isoform of IL18R1 lacks the TIR domain (IL18R1 type II) (Alboni et al. 2009), which is required for signaling, leading to the suggestion that IL18R1 type II is a decoy receptor (Colotta et al. 1994). 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 (Im et al. 2002 , Kim et al. 2002, Novick et al. 1999). IL18BP binds with high affinity to mature IL18, preventing its interaction with IL18R1. Several isoforms IL18BP have been described (Kim et al. 2000). 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 (Boraschi & Dinarello 2006, Park et al. 2007, Dinarello 2007, Dinarello & Fantuzzi 2003).