Interleukin-18 (IL-18), located on chromosome 11 in humans, encodes a 24 kDa polypeptide that was first described in 1989, and is a pro-inflammatorycytokine which induces Type II interferon (IFNg) secretion (Dinarello et al, 2013; Tomura et al, 1998; Nakamura et al, 1989). In 1995, the first cloning of IL-18 took place, along with the name change from IFNg-inducing factor to IL-18, allowing for further analysis of its structure which was found to be similar to IL-1, with human IL-18 and IL-1b sharing a b-pleated structure and exploit the same signaling pathways (Tsutsui et al, 1997; Okamura et al, 1995). Along with IL-1, IL-18 was discovered to be a key mediator of the inflammatory response. Additionally, IL-18 has multiple other functions including the induction of macrophage activation (Giacomini et al, 2001), the maturation of Th1CD4+ T cells (Xu et al, 2000), promoting angiogenesis (Park et al, 2001), and sensitizing cells to apoptosis by increasing the lymphocyte-specific expression of Fas ligand (FasL) (Hashimoto et al, 1999), a potent death receptor agonist.
One of the main similarities between IL-1b and IL-18 is the caspase-1 mediated cleavage of IL-18 in the cytosol, rendering the active 18 kDa form of IL-18 (Ghayur et al, 1997). IL-18 can also be released from cells via pyroptosis, a form of cell death induced by caspase-1 and inflammasome activation. Extracellular IL-18 binds to the membranous a-chain of the IL-18 receptor, forming a complex, however this binding occurs at a relatively low affinity. A higher affinity binding occurs upon ligation of IL-18 with the b-chain of the IL-18 receptor, forming a heterodimeric complex of IL-18, IL-18Ra and IL-18Rb, which leads to the induction of intracellular signalling (Hoshino et al, 1999; Torigoe et al, 1997). Expression of IL-18Ra is ubiquitous, however IL-18Rb expression is more limited and reserved primarily for T cells, macrophages, dendritic cells and some subsets of endothelial cells (Gerdes et al, 2002). Upon receptor activation, the Toll-IL-1 receptor (TIR) domain proteins form a complex at the membrane and downstream signalling through interleukin-1 receptor associated kinases 1,2 and 4 (IRAKs 1,2 and 4) and tumour necrosis factor receptor associated factor 6 (TRAF6), and subsequent degradation of the cytoplasmic inhibitory components of NF-kB, culminating in NF-kB translocation to the nucleus and activation (Akira, 2000; Adachi et a, 1998). IL-18 can also signal to STAT3, inducing its phosphorylation, and also mediate the induction of MAPK signalling (Wyman et al, 2002; Kalina et al, 2000).
Regulation of IL-18
IL-18 binding protein (IL-18BP) is molecule that is constitutively secreted, and, as the name suggests, binds to and neutralizes IL-18, preventing the ligation of IL-18 with IL-18R, thus downregulating IFNg induction. IL-18BP therefore regulates the Th1 response of the immune system, and in infectious pathogeneses the levels of IL-18BP in the serum of patients are not sufficient to neutralize the pro-inflammatory effects of IL-18 (Novik et al, 2001). IL-18BP transcription is under the control of IFNg and therefore acts in a negative feedback loop to regulate IL-18 signalling (Muhl et al, 2000).
Additionally, IL-37 is a secreted cytokine that acts as an inhibitor of the innate immune response by binding to IL-18Ra, but not IL-18Rb, effectively competing with IL-18 for receptor binding (Nold et al, 2010). The mechanism of action of IL-37 is demonstrated to occur via the binding of IL-37 to a complex including IL-18Ra and IL-1R8 (also known as SIGGR) to induce anti-inflammatory responses, thereby combating the effects of IL-18 (Li et al, 2015). Interestingly, IL-18BP also binds to IL-37 and limits its anti-inflammatory effects (Banda et al, 2003).
Diverse biological functions of IL-18
A unique characteristic of IL-18 is the role in the differentiation and maturation of T cells. IL-18, in combination with fellow cytokine IL-12, induces IFNg production in CD4+ and CD8+ single positive T cells, as well as natural killer (NK) cells and macrophages (Nakanishi et al, 2001; Munder et al, 1998). IFNg production occurs via the concurrent IL-18 – dependent stimulation of STAT4 and IL-12 – dependent stimulation of NF-kB (Nakanishi et al, 2001). In the absence of IL-12, IL-18 does not induce IFNg, but instead promotes the differentiation of T cells in Th2 cells (Yoshimoto et al, 2000). IL-18 may negatively regulate Th17 T cells differentiation (Hitzler et al, 2012), however throughout the literature to date this specific role remains unclear.
Furthermore, IL-18 induces the cytotoxicity of NK cells in a FasL-dependent manner (Tsutsui et al, 1996). The ability of IL-18 to upregulate FasL may mediate severe pathogenic conditions, such as fever (Gatti et al, 2002). In addition to the IFNg – centric functions of IL-18, an increase in nitric oxide synthesis, increased cell adhesion molecules and elevated levels of chemokines are all described in response to IL-18 stimulation (Morel et al, 2001; Kohka et al, 1998).
Pathogenesis of IL-18
IL-18 has been identified to have a role in multiple infectious, metabolic or inflammatory diseases, such as Crohn’s disease, inflammatory bowel disease, influenza virus and chronic obstructive pulmonary disease (COPD) (Imaoka et al, 2008; Naftali et al, 2007; Saraneva et al, 1998). Additionally, elevated levels of IL-18 in post-operative patients are indicative of sepsis pathogenesis (Emmanuilidis et al, 2002). Under homeostatic conditions in the gut, IL-18 is produced by endothelial cells, facilitating the maintenance of a healthy microbiota. However, pathogen-induced secretion of IL-18 from macrophages occurs upon disruption of the intestinal barrier in inflammatory bowel disease and initiates a robust pro-inflammatory response (Lissner et al, 2015). As IL-18 has many diverse physiological functions, targeting IL-18 for use as a therapeutic currently is limited, however, it has proven to be a valid biomarker for multiple pathogeneses.
Figure 1: IL-18 signalling. IL-18 binds to the membrane-bound IL-18R a subunit with low affinity, however upon binding to the IL-18R b subunit, a complex is formed and intracellular signalling through the TIR adaptor proteins, IRAK and TRAF6 lead to downstream degradation of the NF-kB inhibitory subunits and subsequent nuclear translocation and activation of NF-kB. IL-18 can be neutralized extracellularly by the secreted IL-18 binding protein (IL-18BP), and IL-18 ligation to the IL-18R a subunit can be inhibited by IL-37.
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