IL-18 signaling is regulated by caspase 6/8 and IL-18BP in turbot (Scophthalmus maximus).

• Published in: International Journal of Biological Macromolecules
• Main Authors: Yu, Chao, Xu, Hang, Jiang, Shuai, Sun, Li
• Format: Article in Journal/Newspaper
• Language: English
• Published: Elsevier Science 2024
• Subjects: Caspase; Immune defense; Interleukin 18; Interleukin 18 binding protein; Interleukin 18 receptor; Teleost; Scophthalmus maximus; Turbot
• Online Access: https://doi.org/10.1016/j.ijbiomac.2024.135015; https://pubmed.ncbi.nlm.nih.gov/39181350

Interleukin (IL)-18 is synthesized as a precursor that requires intracellular processing to become functionally active. In human, IL-18 is processed by caspase 1 (CASP1). In teleost, the maturation and signal transduction mechanisms of IL-18 are unknown. We identified two IL-18 variants, IL-18a and IL-18b, in turbot. IL-18a, but not IL-18b, was processed by CASP6/8 cleavage. Mature IL-18a bound specifically to IL-18 receptor (IL-18R) α-expressing cells and induced IL-18Rα-IL-18Rβ association. Bacterial infection promoted IL-18a maturation in a manner that required CASP6 activation and correlated with gasdermin E activation. The mature IL-18a induced proinflammatory cytokine expression and enhanced bacterial clearance. IL-18a-mediated immune response was suppressed by IL-18 binding protein (IL-18BP), which functioned as a decoy receptor for IL-18a. IL-18BP also functioned as a pathogen pattern recognition receptor and directly inhibited pathogen infection. Our findings revealed unique mechanism of IL-18 maturation and conserved mechanism of IL-18 signaling and regulation in turbot, and provided new insights into the regulation and function of IL-18 related immune signaling.