First printed in R&D Systems' 1998 Catalog.
The regulation of interferon-gamma (IFN-gamma) synthesis is one of the most tightly controlled processes of an immune response. Production of IFN-gamma, a 34 kDa homodimeric glycoprotein, is essentially restricted to activated CD4+ Th1 T cells, CD8+ TC1 T cells, and NK cells.1, 2 For each cell type, IFN-gamma secretion is further restricted by the availability of IFN-gamma-inducing cytokines such as IL-12 and TNF-alpha, which arise from accessory cells following activation.1 One of the most important consequences of IFN-gamma secretion is the activation of macrophages. This is achieved through the induction of reactive oxygen intermediates and nitrogen monoxide (NO), which activate a variety of anti-bacterial, anti-tumor and anti-viral responses.1 In addition, IFN-gamma contributes to endothelial cell activation, Th1 cell development, and upregulation of MHC expression on both professional APCs and non-APCs. This makes the regulation of IFN-gamma an extremely important step in the overall scheme of an inflammatory response.1, 3
With the discovery of IL-18 (also known as interferon-gamma inducing factor, or IGIF), a new molecule has now been added to the very short list of interferon regulators.4, 5 Aside from molecules such as IL-12, TNF-alpha, and IL-2, few, if any, other cytokines are currently known that directly induce the expression of IFN-gamma.1, 6 The existence of this new interleukin may help in understanding the many events associated with immune cell activation.
IL-18 is a 24 kDa, non-glycosylated polypeptide that lacks a classical signal sequence4, 5, 7, 8 and possesses a structure recognizably similar to IL-1.5, 7 IL-18 is synthesized as a bio-inactive propeptide that undergoes proteolytic cleavage by either ICE (interleukin-1 beta converting enzyme) or another caspase to generate a mature, bioactive, 18 kDa molecule.5, 8, 9 Cleavage within the 193 amino acid (aa) human propeptide occurs after Asp #36, while cleavage within the 192 aa mouse propeptide occurs after Asp #35.5, 9 In both the mature and propeptide forms, IL-18 shows 64% aa sequence identity from mouse to human.5 IL-18 does not appear to show any primary sequence similarity to any other known cytokines.4, 7 Rat IL-18 has also been isolated, and found to be 194 aa in length with a 91% aa sequence identity to mouse IL-18.10 Notably, the rat IL-18 gene seems to undergo alternative splicing since a 175 aa shorter form has also been identified.10 The molecule appears to be species specific. Cells known to express IL-18 include macrophages/Kupffer cells,4, 11 keratinocytes,12 glucocorticoid-secreting adrenal cortex cells,10 and osteoblasts.13
The receptor complex for IL-18 is not yet well characterized. Recent evidence suggests that a functional IL-18-binding component of this complex is IL-1Rrp (IL-1 receptor-related protein).13 This receptor-like protein, which previously had no known ligand, was cloned n the basis of its homology to the Type I IL-1 receptor and its homologs T1/ST2 and IL-1R AcP.14
As suggested by its name, IL-18/IGIF was initially recognized as a potent inducer of IFN-gamma production by T-cells4, 15 and apparently, NK cells.16 Either independently or in synergy with IL-12, the effects of IL-18, through its induction of IFN-gamma, can lead to a rapid activation of the monocyte/macrophage system with an upregulation of these cell's innate immune capabilities.1, 17 IL-18 itself is induced by stressful stimuli (i.e., bacterial or neurogenic signals).4, 10 In this context, it has been proposed that a stress-induced release of IL-18 can lead to a reinforcing cycle of IFN-gamma/IL-18 production. Following an initial wave of IL-18-induced IFN-gamma production, newly secreted IFN-gamma can now stimulate monocytes/macrophages to increase their ICE activity. In the presence of continued IL-18 production, increased ICE activity probably results in more processed IL-18, which leads to more lymphocyte IFN-gamma production, which leads to more macrophage ICE activity, etc.8 Thus, IL-18 not only promotes IFN-gamma synthesis, but also likely participates in its overall activities.
IL-18 has also been implicated in killing mediated by the Fas ligand (FasL). FasL is a tightly regulated 40 kDa member of the TNF superfamily of molecules (see mini-review, page 21).18 The binding of FasL to its widely expressed receptor, Fas, usually leads to activation of an apoptotic program in the cell expressing Fas.19 In the adult immune system, this outcome is often used to eliminate unwanted cells that may interfere with either an ongoing immune process or an immune reaction undergoing resolution.16, 20 Cells that are believed to mediate such activities are CD4+ Th1 cells and NK cells, two cell populations that are now reported to express FasL under the influence of IL-18.16, 21 In this respect, IL-18 again demonstrates a relationship to IFN-gamma. It appears that IFN-gamma is an upregulator of Fas antigen expression.22 IL-18 upregulates both FasL and IFN-gamma production in T cells and the IFN-gamma produced may well induce Fas antigen on a variety of cell types. Thus IL-18, via IFN-gamma induction, could be considered a molecule that provides both the means (FasL) and the opportunity (Fas) for instigating apoptotic cell death
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