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IL18

[Interleukin-18] The gene encoding this nonglycosylated protein of 24 kDa has been identified originally as IGIF (IFN-gamma inducing factor). It encodes an inducer of IFN-gamma production by T-cells (Okamura et al, 1995; Micalef et al, 1997) and natural killer cells (Tsutsui et al, 1996) that is a more potent inducer than IL12. Alternative designations are IL1-gamma and IL1F4. Human recombinant IL18 is marketed as Iboctadekin (GlaxoSmithKline).

The proteins from murine (192 amino acids) and human IL18 (193 amino acids) sources show 65 % homology. Rat and murine IL18 display 91 % homology (nucleotide and amino acid level). IL18 does not display sequence similarities to other known proteins but a survey of the sequence by fold recognition methods demonstrates that it belongs to the IL1 family of cytokines (Ushio et al, 1996).

IL18 lacks a classical signal sequence necessary for secretion (Okamura et al, 1995; Ushio et al, 1996; Gu et al, 1997). IL18 is synthesized as a biologically inactive precursor protein that has limited biological activity. The proform of IL18 is processed by one of the caspases, Caspase-1, to generate the 18 kDa bioactive molecule (Gu et al, 1997; Ghayur et al, 1997). Other proteases such as neutrophil proteinase-3 (Myeloblastin) may provide activation pathways that are independent of caspases (Sugawara et al, 2001).

Kikkawa et al (2001) have demonstrated that monocytes and macrophages produce large amounts of various IL18 species. Some of them are inactive dimers while others have weak IFN-gamma inducing activity. IL18 type 2 is a fragment of IL18 that possesses little activity as an inducer of IFN-gamma. This variant is bound to IgM in plasma and is found at high levels in approximately 30 % of normal subjects (Shida et al, 2001). The authors suggest that this variant may play some roles in the development of Th2 cell responses involving IgE production in association with atopic lesions.

The human gene has been mapped to chromosome 11q22.2-q22.3 (Nolan et al, 1998).

IL18 is produced during the acute immune response by macrophages and immature dendritic cells. IL18 is expressed by a variety of immune and non-immune cells, including monocytes and macrophages (Okamura et al, 1995; Ushio et al, 1996), Kupffer cells (Okamura et al, 1995; Seki et al, 2001), T-cells and B-cells (Nakanishi et al, 2001); Klein et al, 1999), dendritic cells (Stober et al, 2001; Gardella et al, 2000; Stoll et al, 1998; de Saint-Vis et al, 1998), osteoblasts (Udagawa et al, 1997; Torigoe et al, 1997), epidermal keratinocytes (Stoll et al, 1997), intestinal epithelial cells (Takeuchi et al, 1997; Pizarro et al, 1999), corneal epithelial cells (Burbach et al, 2001), glucocorticoid-secreting adrenal cortex cells (Conti et al, 1997), astrocytes, and microglial cells (Conti et al, 1999; Suk et al, 2001).

Acute cold stress strongly induces IGIF gene expression in rats (Conti et al, 1997). rat IGIF has been shown to be expressed in the adrenal gland of reserpine-treated rats (Conti et al, 1997). Park et al (2001) have reported an enhanced IL18 expression in common skin tumors.

IL18 is one of the pro-inflammatory cytokines. The activities of IL18 appear to be species specific. An important function of IL18 is the regulation of functionally distinct subsets of T-helper cells required for cell mediated immune responses (Nakanishi et al, 2001). IL18 functions as a growth and differentiation factor for Th1 cells. IL18 upregulates FAS ligand mediated cytotoxic activitiy of murine natural killer cells (Tao et al, 1996; Tsutsui et al, 1996). IL18 is part of a complex regulatory circuit involved in causing cell death by apoptosis. The expression of the receptor for FAS ligand, FAS antigen, is upregulated by IFN-gamma (Watanabe-Fukunaga et al, 1992) that itself is induced by IL18.

IL18 is a pleiotropic cytokine. IL18 induces activated B-cells to produce IFN-gamma that inhibits IgE production (Yoshimoto et al, 1997). IL18 has been shown to strongly augment the production of IFN-gamma by T-cells and NK-cells (Micallef et al, 1996). The ability of IL18 to enhance IFN-gamma production by NK-cells is dependent on the presence of IL12 (Walker et al, 1999). IGIF enhances T-cell proliferation apparently through an IL2 dependent pathway (Micallef et al, 1996).

Park et al (2001) have shown that IL18 is an angiogenic mediator that induces migration of microvascular endothelial cells and causes tube formation by endothelial cells in a matrigel matrix in vitro. It also induces angiogenesis in vivo in a matrigel plug assay.

IL18 has been found to enhance also the production of GM-CSF. Udagawa et al (1997) have shown that IL18 produced by osteoblastic stromal cells acts via GM-CSF and not via IFN-gamma to inhibit osteoclast formation.

Morel et al (2001) have observed that IL18 induces the expression of the CXC-Chemokines IL8, MGSA, ENA-78 in rheumatoid arthritis synovial fibroblast. It does not appear to induce the production of MIP-1-alpha.

IL18 inhibits osteoclast formation via T-cell production of GM-CSF (Udagawa et al, 1997; Horwood et al, 1998, 2001).

By stimulating immune cells IL18 also exibits a strong antitumoral activity, protecting experimental animals against repeated challenges with tumor cells cells (Micallef et al, 1997). In an attempt of cancer gene therapy, Osaki et al (1999) have introduced the IL18 gene into murine tumors and observed a potent antitumor effects mediated by local expression of IL18. Kishida et al (2001) have reported that the simultaneous expression of IL18 and IL12 by engineered melanoma cells induces significant antitumor effects in mice.

A protective effect of IL18 against the development of chronic graft-versus-host disease in the mouse has been demonstrated by Okamoto et al (2000). Reddy et al (2001) have shown that the inhibition of Il18 accelerates mortality caused by acute graft-versus-host disease in a bone marrow transplant model and that is due to increased FAS antigen mediated donor T-cell apoptosis. Leung et al (2001) have demonstrated that IL18 activates human neutrophils and that IL18 administration promotes accumulation of neutrophils in vivo, whereas IL18 neutralization suppresses the severity of footpad inflammation following carrageenan injection.

Abnormal expression of IL18 has been observed in autoimmune non obese diabetic (NOD) mice and to be closely associated with development of diabetes (Rothe et al, 1997). Pizarro et al (1999) have detected increased IL18 mRNA and protein expression that intestinal epithelial cells and lamina propria mononuclear cells in Crohn's disease tissue express elevated levels of IL18.

IL18 mediates infection resistance against a variety of pathogens, mainly due to the induction of IFN-gamma expression. IL18 plays a critical role in the defense against intracellular bacteria, including Listeria, Shigella, Salmonella, and Mycobacterium tuberculosis (Biet et al, 2002). Liver damage in mice caused by treatment with Propionibacterium acnes and septic shock induced by challenge with lipopolysaccharides can be prevented by administration of anti-IGIF antibodies (Okamura et al, 1995).

IL18, together with other cytokines, may play a role in the development of hepatic metastases of melanoma in vivo through upregulating the expression of vascular cell adhesion molecule 1 and melanoma cell adherence (Vidal-Vanaclocha et al, 2000).

IL18 appears to play a direct neuromodulatory role in synaptic plasticity and impairs long-term potentiation and NMDA receptor mediated transmission in the rat hippocampus in vitro (Curran et al, 2001).

The expression of functional IL18 and IL18 receptor on human atheroma-associated endothelial cells, smooth muscle cells, and mononuclear phagocytes, and its ability to induce IFN-gamma expression in smooth muscle cells, suggests a paracrine pro-inflammatory role in atherogenesis (Gerdes et al, 2002).

Ogura et al (2001) have reported that IL18 stimulates CD4(+) T-cells and macrophages to secrete IL5, GM-CSF, IL6, and G-CSF in the absence of IL12, which in turn induces hematopoietic cell proliferation causing neutrophilia and eosinophilia in mice.

Wang et al (2001) have reported that vaccination with IL18 gene-modified, superantigen-coated tumor cells elicits potent antitumor immune responses.

TRANSGENIC ANIMALS, KNOCK-OUT, AND ANTISENSE STUDIES

Wei et al (1999, 2001) have generated transgenic knock-out mice lacking expression of IL18. These mice are viable and fertile. There are no evident histopathologic abnormalities. The animals are susceptible to infections by the protozoan parasite Leishmania major. Infected mice produce significantly lower levels of IFN-gamma and larger amounts of IL4 compared with similarly infected heterozygous or wild-type mice. Infections of knock-out mice with Staphylococcus aureus, are less severe than similar infections in wild-type mice. Mutant mice develop significantly more severe septic arthritis than control mice. This is accompanied by a reduction in the levels of antigen induced splenic T-cell proliferation, decreased synthesis of IFN-gamma and TNF-alpha, but increased production of IL4.

Wei et al (1999, 2001) also have reported a reduced incidence and severity of collagen induced arthritis in mice lacking IL18 and that treatment with recombinant IL18 completely reverses the disease of the IL18 knock-out mice to that of the wild-type mice.

RECEPTORS

A functional component of the human receptor for IGIF has been identified in the Hodgkin's disease cell line, L428 (Torigue et al, 1997). The cells express approximately 18,000 binding sites/cell. The dissociation constant of IL18 binding to L428 cells is about 18.5 nM. The cloned receptor component was shown to be identical with IL1Rrp [IL1 receptor-related protein). Expression of the IL1Rrp cDNA in COS-1 cells has been shown to confer IL18 binding properties on the cells and the capacity for signal transduction. This receptor is being referred to now as IL18R1 [interleukin-18 receptor-1; IL18R-alpha] or IL18RA [interleukin-18 receptor-alpha].

Debets et al (2000) have shown that a highly specific IL18 receptor is formed together with IL1RAPL [IL1 receptor accessory protein-like]. This receptor is the same as IL18RAP [IL18 receptor accessory protein], which is the approved gene symbol for a protein that has been described also as AcPL [accessory protein-like subunit]. The protein is being referred to also as IL18RB [IL18R-beta].

Some of the bioactivities of IL18 are modulated by a secreted binding protein, IL18BP [IL18 binding protein].

DETECTION AND ASSAY METHODS

Taniguchi et al (1997) have developed an ELISA (see also: cytokine assays) specific for human IL18 ELISA. This assay has a minimum detection limit of 10 pg/mL and does not react with heat-denatured human IL18. There is no cross-reactivity with other cytokines. Taniguchi et al (1998) have established also cells useful for bioassays of murine IL18 by transfection of the murine IL18 receptor gene into KG-1 cells. Konishi et al (1997) have described sensitive bioassays for human IL18 using the human myelomonocytic cell line, KG-1.


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ENTRY LAST MODIFIED: March 2002



 

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