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 a ligand protein which has to be processed to become active. It is synthesized as an inactive 24-kDa precursor protein and after be cleaved by caspase-1 (or other extracelullar enzymes as protease 3, serine protease, elastase and cathepsine G (Fantuzzi & Dinarello 1999,Gracie et al. 2004, Sugawara et al. 2001) it becomes to a 18-kDa mature and secretable 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).
Also exists a short isoform of IL18 resulting from alternative splicing removing 57 bp/19 aa (IL18?, IL18 alpha isoform) (Conti et al. 1997, Yang et al.2005). It is suggested this short isoform has a modest synergistic action with IL18 canonical active form. On the other hand the IL18 receptor (IL18R) belongs to the Interleukin-1 receptor/Toll like receptor superfamily. It is comprised of two subunits, Interleukin-18 receptor 1 (IL18R1, IL-18R?, IL1Rrp1, IL18R1 or IL-1R5) and (IL18RAP,IL-18R?,IL-18RacP, IL-18RII or IL-1R7) both with three extracellular immunoglobulin-like domains and one intracellular Toll/IL-1 receptor (TIR) domain (O'Neill & Dinarello 2000, Sims 2002). It is believed 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). Also, there are isoforms as a short transcript for IL18R1 encoding for a receptor subunit lacking the TIR domain (IL18R1 type II) (Alboni et al. 2009). The TIR domain is required for signaling so IL18R1 type II is suggested to be a decoy receptor (Colotta et al. 1994). Moreover, a truncated form of IL18RB (IL18RB) comprising only one of the three immunoglobulin domains stabilizes IL18 binding to IL18R1 preventing signaling (negative regulator).
IL-18 binding protein (IL18BP) is 38-kDa soluble protein is another negative regulator with some sequence homology with IL18R1 (Im et al. 2002 , Kim et al. 2002, Novick et al. 1999). IL18BP binds selectively and with high affinity to mature IL18 preventing its interaction with IL18R1. Several isoforms of this protein have been described (Kim et al. 2000). Interleukin-37 (IL37, IL-1F7) is another negative regulator of IL18 because it is able to bind IL18BP and IL18RAP chain preventing the cascade signaling (Bufler et al.2002, Pan et al. 2001, Kumar et al. 2002).
Finally IL18 stimulates Interferon gamma (IFNG, IFN-?) production from T-helper lymphocytes cells (Th1) and macrophages, and enhances the cytotoxicity of natural killer (NK) cells. The IL18 stimulated IFNG production is synergistically amplified with other Th1-related cytokines, IL2, IL15, IL12 and IL23 (Boraschi & Dinarello 2006, Park et al. 2007, Dinarello 2007, Dinarello & Fantuzzi 2003).