IL-18:: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family

Formerly called IFN-gamma-inducing factor, II-IS is the new name of a novel cytokine that plays an important role in the T-H1 response, primarily by its ability to induce IFN-gamma production in T cells and natural killer cells. Mice deficient in IL-18 have suppressed IFN-gamma production despite the presence of IL-12, IL-18 is related to the IL-1 family in terms of both structure and function. In terms of structure, IL-18 and IL-1 beta share significant primary amino acid sequences and are similarly folded as all-beta pleated sheet molecules. Also similar to IL-1 beta, IL-18 is synthesized as a biologically inactive precursor molecule lacking a signal peptide, Studies have shown that similar to the IL-1 beta precursor, the IL-18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease called IL-1 beta-converting enzyme (ICE), which is also known as caspase-1, Therefore inhibitors of ICE activity may limit the biologic activity of IL-18 and may be useful as T-H1 immunosuppressive agents. The activity of mature IL-IS is closely related to that of IL-1, IL-18 induces gene expression and synthesis of TNF, IL-I, Fas ligand, and several chemokines, The activity of IL-18 is by means of a signaling chain of a putative IL-18 receptor (IL-18R) complex, This IL-18R complex is made up of a binding chain termed IL-18R alpha, a member of the IL-IR family previously identified as the IL-1R-related protein (IL-1Rrp), and a signaling chain, the IL-18R beta, also a member of the IL-IR family. The IL-18R complex recruits IL-1R-activating kinase and TNF receptor-associated factor-6, which phosphorylates nuclear factor kappa B (NF kappa B)-inducing kinase with subsequent activation of NF kappa B, Thus on the basis of primary structure, 3-dimensional structure, receptor family, signal transduction pathways, and biologic effects of IL-18 appear to place this cytokine in the IL-l family. Similar to IL-1, IL-18 participates in both innate and acquired immunity.