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.
An important role of IL-18 has been shown in clinical implications, in the role of IL-18 modulation in tumours, infections, and autoimmune and inflammatory diseases.
Elevated serum levels of IL-18 have been shown in patients with acute graft-versus-host disease after bone marrow transplantation.
Highly elevated IL-18 bioactivity with highly elevated serum IL-18 levels are measured in hematological malignancies as well as in sepsis.
Increased concentrations of plasma IL-18 are found in patients with hepatic dysfunction after hepatectomy and in inflammatory liver diseases. Elevations of IL-18 levels accompany autoimmune disorders like systemic lupus erythematosus and rheumatoid arthritis.
Significant levels of circulating IL-18 are found in HIV-1 infection, and other infections, in inflammatory CNS diseases, in Crohn?s disease and in pregnancy during labour and complicated pregnancies.
IL-18 is regarded as a novel player in tumour immunotherapy.
Okamura H., et al. Nature 378, 88-91 (1995)
Ushio S., et al. J. Immunol. 156, 4274-4279 (1996)
Micallef M., et al. Eur. J. Immunol. 26, 1647-1651 (1996)
Tao D, et al. Cell Immunol. 173, 230-235 (1998)
M. Taniguchi, et al. J. Immunol. Methods 206, 107-113 (1997)
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