Interleukin-18 (IL18, pro-IL18) is a pleiotropic and pro-inflammatory cytokine. It belongs to the Interleukin-1 (IL1) superfamily (28352119 ,9893178, 7477269).
IL18 is a ligand protein which has to been 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 [17-19]) it becomes to a 18-kDa mature and secretable protein [4,12-16].
Also exists a short isoform of IL18 resulting from alternative splicing removing 57 bp/19 aa (IL18?, IL18 alpha isoform)  . 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 immunoglobuling-like domains and one intracellular Toll/IL-1 receptor (TIR) domain [22,23]. It is believed IL18 binds first to IL18R1 and later recruits IL18RAP to form a high-affinity heterotrimeric complex [23-25]. Also there are isoforms as a short transcript for IL18R1 encoding for a receptor subunit lacking the TIR domain (IL18R1 type II) . The TIR domain is required for signaling so IL18R1 type II is suggested to be a decoy receptor . 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 [30-32]. IL18BP binds selectively and with high affinity to mature IL18 preventing its interaction with IL18R1. There are described also idoforms of this protein .
Interleukin-37 (IL37, IL-1F7) is another negative regulator of IL18 because it is able to bind IL18BP and and IL18RAP chain preventing the cascade signaling [34, 37,40].
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[5,6,7,8].