Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines. Similar to IL-1β, IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine, but unlike IL-1β, the IL-18 precursor is constitutively present in all cells in healthy humans and animals. The activity of IL-18 is balanced by the presence of a high affinity, naturally occurring IL-18-binding protein (IL-18BP). 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-1beta-converting enzyme (ICE, also called caspase-1). The activity of 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. The activity of IL-18 is via an IL-18 receptor (IL-18R) complex. This IL-18R complex is made up of a binding chain termed IL-18Ralpha, 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 TNFR-associated factor-6 (TRAF-6) which phosphorylates nuclear factor kappa-B (NF-kB)-inducing kinase (NIK) with subsequent activation of NFkB.
Physiological Role in the Immune System
Interleukin-18 (IL-18) was first described in 1989 as “IFNγ-inducing factor” isolated in the serum of mice following an intraperitoneal injection of endotoxin. Days before, the mice had been pretreated with Propionibacterium acnes, which stimulates the reticuloendothelial system, particularly the Kupffer cells of the liver. Many investigators concluded that the serum factor was IL-12. With purification from mouse livers and molecular cloning of “IFNγ-inducing factor” in 1995, the name was changed to IL-18 (Berasain et al. 2009).
IL-18 is predominantly produced by macrophages and dendritic cells. This chemokine is able to amplify the innate immune response by inducing the expression of cytokines including granulocyte–macrophage colony-stimulating factor (GM-CSF), TNF-α, IL-1β, and chemokine such as IL-8 by peripheral blood mononuclear cells. IL-18 also induces granule formation in neutrophils, Fas ligand expression on T cells and NK cells, and apoptosis in Fas-expressing cells. The major biological function of IL-18 is to increase IFN-γ production by T cells and to promote the differentiation of IFN-γ-producing (Th1) CD4+ T cells.
Together with IL-12, IL-18 participates in the Th1 paradigm. This property of IL-18 is due to its ability to induce IFNγ either with IL-12 or IL-15. Without IL-12 or IL-15, IL-18 does not induce IFNγ. IL-12 or IL-15 increases the expression of IL-18Rβ, which is essential for IL-18 signal transduction. Importantly, without IL-12 or IL-15, IL-18 plays a role in Th2 disease. The importance of IL-18 as an immune-regulatory cytokine is derived from its prominent biological property of inducing IFNγ from NK cells.
Very recent data support the autocrine role of IL-12 and IL-18 on IFN-γ production in human monocytes and macrophages, indicating a possible role of IL-12 and IL-18 in T- and NK-independent innate immune responses. Although IL-18 is a potent inducer of IFN-γ production by Th1 cells, unlike IL-12, it is not able to induce Th1 development by itself. The importance of cooperative activity of IL-18 and IL-12 in both IFN-γ and Th1 production was confirmed by in vivo studies using mice lacking one or both of these cytokines. IFN-γ production by IL-18 and IL-12 stimulation is important in the modulation of the naïve T helper cell maturation towards a Th1 profile. Th1 immune response is activated primarily by IL-2, IL-12, IFN-γ, and TNF-β, which are secreted during cytotoxic T cells (CTLs) or NK cell-mediated immune response (Dobrovolskaia and Kozlov 2005). Th1 responses are prominent in some autoimmune disorders, graft rejection, and antitumor immunity. In normal conditions, Th1 response is balanced by a Th2 response acting as a regulatory mechanism. Therefore, Th2 cytokines (IL-4, IL-5, IL-6, and IL-10) lead to local recovery of homeostasis, B cell maturation, and antibody production. In pathologic conditions, such as in cancer, this balance is broken and the prevalence of Th2 responses can help cancer cells to escape immune surveillance by hampering CTL function and inducing their apoptosis. Interleukin-18 can rescue CTL activity and survival. Furthermore, IL-12 and IL-18 selectively induce the production of monocyte neutrophil and T and NK cell-attracting chemokines CXCL8, CXCL9, and CXCL10, but not CCL3, CCL4 and CCL5. A striking difference between these two groups of chemokines is that only the former have known pro-angiogenic (CXCL8) or angiostatic (CXCL9 and CXCL10) properties (Coma et al. 2006). In addition to its effect on IFN-γ production, IL-18 is also able to stimulate Th2 responses. In fact, IL-18 promotes IgE expression and Th2 differentiation and together with IL-2 enhances the production of IL-13 by cultured T lymphocytes and NK cells. IL-18 can potentially induce IgG1, IgE, and Th2 cytokines such as IL-4, IL-5, and IL-10 production in murine experimental models. More recently, it has been demonstrated that IL-18, in synergy with IL-23, drives Th17 cell polarization. A high ratio of effectors CD8+ T cells versus Tregs in the tumor microenvironment can be a favorable prognostic feature in patients with ovarian cancer, and an increase in the ratio of CD8+ T effectors to regulatory cells, in syngeneic mouse tumor models and in humans with cancer, is correlated with responses to immunotherapies (Quezada et al. 2006).
Role in Cancer
IL-18 is a multifunctional cytokine, which has been investigated for both its precancerous and anticancer activities. Han et al. reported that IL-18 gene promoter polymorphism is a genetic risk factor for several types of cancer (Han et al. 2004). Variations in the DNA sequence in the IL-18 gene promoter may lead to altered IL-18 production, and so this can modulate an individual’s susceptibility. Cytokines have a key role by exerting tumor and antitumor properties in the biological processes of tumors. The balance between pro-inflammatory and anti-inflammatory cytokines is responsible for the presence and intensity of cancer progression. IL-18 is a pro-inflammatory cytokine and plays a central role in tumor migration, invasion, and metastasis with dual effects on tumor development and progression. In fact, it increases the escape immune recognition and induces production of angiogenic and tumor growth-stimulating factors. The role of IL-18 in cancer progression remains controversial, and the regulation of the IL-18 secretion is an important step in tumor progression.
IL-18 in Cancer Progression
The first evidence that IL-18 promotes cancer growth comes from the observation of elevated IL-18 expression or secretion by cancer patients. IL-18 was expressed and secreted in common skin tumors including squamous cell carcinoma (SCC) and melanoma cell lines. Thus, the expression of IL-18 by tumor cells in human skin tissue may provide an important clue to the understanding of pathogenesis of malignant skin tumors (Park et al. 2001).
High levels of IL-18 production may play a major role in the growth and metastasis of renal cancer. Higher expression of IL-18 is detected in various cancer cells. Serum IL-18 level was a significant and independent prognostic factor of survival in hepatocellular carcinoma. Interleukin-18-binding protein (IL-18BP), a potent inhibitor of interleukin 18, is significantly upregulated in several diseases. Kim et al. described (2008) the mechanism of action of IL-18 in cancer progression. Hypoxia induces the transcription and secretion of IL-18, which subsequently induces the expression of hypoxia-inducible factor-1alpha (HIF-1α) by activating the GTPase Rac. HIF-1α mediates tumor progression, so the induction of IL-18 by hypoxia or inflammatory cells augments the expression of both HIF-1alpha and tumor cell metastasis.
IL-18 and Metastasis
Cancer cells metastasize after escaping from the immune system, and CD70, CD44, and vascular endothelial growth factor (VEGF) play important roles in this process. Endogenous IL-18 facilitate cancer cell immune escape by suppressing CD70 and increasing metastatic potential by upregulating CD44 and VEGF. Chandrasekar et al. (2006) and Jiang et al. observed a lung cancer metastasis model (Jiang et al. 2003) in which IL-18 induces expression of metalloproteinase-9 (MMP-9) and MMP2 mRNA and protein levels which are considered important extracellular matrix-degrading enzyme (ECM-degrading enzyme). IL-18 can enhance Fas ligand expression and suppress the immune system. Fas ligand-mediated immune suppression was proposed in melanoma cells. Based on the evidence that in melanoma reactive oxygen intermediates (ROI) play a key role in the induction of resistance to Fas-mediated cell death, Cho et al. (2000) hypothesized that IL-18 might be produced in melanoma cells and act as an autocrine factor to regulate Fas ligand expression and intracellular ROI production for immune escape. The results obtained showed that endogenous IL-18 modulates immune escape of murine melanoma cells by regulating the expression of Fas ligand and reactive oxygen intermediates (Clement and Stamenkovic 1996).
Il-18 and Anticancer Effects
It has been demonstrated that IL-18 exerts antitumor effects which are mediated by apoptosis induction and angiogenesis inhibition (Coughlin et al. 1998). Recently, several reports have shown that IL-18 has potent antitumor effects when administered in animal models of lung cancer, breast cancer, sarcoma, lymphoma, and melanoma in vivo. In these models, systemic administration of IL-18 (Wang et al. 2001) or in vivo IL-18 gene transfer (Akamatsu et al. 2002) inhibited tumor growth and prolonged the survival of tumor-bearing mice. These reports indicate that IL-18 has potent antitumor effects mediated by T cell and NK cells that are in part IFNγ and IL-12 independent and Fas–Fas ligand and perforin dependent (Osaki et al. 1999).
Resistance to chemotherapy is the major cause of failure in cancer treatment. Immunotherapy represents a promising approach to overcome the limitation of anticancer drugs and improve their clinical efficacy. The cytokines associated with drug resistance may represent potential biomarkers or new therapeutic targets (Alagkiozidis et al. 2011). Serum IL-18 concentration predicted the clinical outcome of patients with aggressive non-Hodgkin’s lymphoma in treatment with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP).
In the last few years, the field of tumor immunology has significantly expanded and its boundaries, never particularly clear, have become less distinct. Although the immune system plays an important role in controlling tumor growth, it has also become clear that tumor growth can be promoted by inflammatory immune responses. A good example that exemplifies the ambiguous role of the immune system in cancer progression is represented by interleukin 18 (IL-18) that was first identified as an interferon-γ-inducing factor (IGIF) involved in T helper type 1 (Th1) immune response. The expression and secretion of IL-18 have been observed in various cell types from immune cells to circulating cancer cells.
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