Description
Interleukin (IL) -18 is a newly discovered cytokine, structurally similar to IL-1, with profound effects on T-cell activation. Formerly called interferon (IFN) gamma inducing factor (IGIF), IL-18 is a novel cytokine that plays an important role in the T-cell-helper type 1 (Th1) response, primarily by its ability to induce IFN gamma production in T cells and natural killer (NK) cells. In terms of structure, IL-18 and IL-1 beta share primary amino acid sequences of the so-called „signature sequence“ motif 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 which requires cleavage into an active, mature molecule by the intracellular cysteine protease called IL-1 beta-converting enzyme (ICE, caspase-1). Therefore inhibitors of ICE activity may limit the biologic activity of IL-18 and may be useful as Th1 immunosuppressive agents. The activity of the mature IL-18 is closely related to that of IL-1. IL-18 induces gene expression and synthesis of tumor necrosis factor (TNF), IL-1, Fas Ligand, and several chemokines. IL-18 induces the differentiation of Th1 or Th2 cells depending upon cytokine milieu and genetic background. The activity of IL-18 is via an IL-18 receptor (IL-18R) complex. This complex is made up of a binding chain termed IL-18R, a member of the IL-1 receptor family previously identified as the IL-1 receptor – related protein (IL-1Rrp), and a signaling chain, also a member of the IL-1R family. The IL-18R complex recruits the IL-1R – activating kinase (IRAK) and TNF-R – associated factor –6 (TRAF-6) with subsequent activation of NF kappa B. Thus based on primary structure, three-dimensional structure, receptor family, signal transduction pathways and biological effects, IL-18 appears to be a new member of the IL-1 family. Similar to IL-1, IL-18 participates in both innate and acquired immunity. Constitutive IL-18 expression is detected from many different cells, including macrophages, keratinocytes, and osteoblasts. Human keratinocytes have been found to be the major producers of IL-18 in unprocessed form