Cytokines usually contain the signal peptide which is necessary for their
extracellular release. In this case, the IL18gene, similar to other
IL-1 family members, lacks this
signal peptide.[11] Furthermore, similar to
IL-1β, IL-18 is produced as a biologically inactive
precursor. IL-18 gene encodes for a 193
amino acids precursor, first synthesized as an inactive 24
kDa precursor with no signal peptide, which accumulates in the cell
cytoplasm. Similarly to IL-1β, the IL-18 precursor is processed intracellularly by
caspase 1 in the
NLRP3inflammasome into its mature biologically active molecule of 18 kDa.[12]
Receptor and signaling
IL-18
receptor consists of the
inducible component IL-18Rα, which binds the mature IL-18 with low
affinity and the
constitutively expressedco-receptor IL-18Rβ. IL-18 binds the
ligand receptor IL-18Rα, inducing the recruitment of IL-18Rβ to form a high affinity complex, which signals through the
toll/interleukin-1 receptor (TIR) domain. This signaling domain recruits the
MyD88adaptor protein that activates
proinflammatory programs and
NF-κB pathway. The activity of IL-18 can be suppressed by extracellular interleukin 18 binding protein (
IL-18BP) that binds
soluble IL-18 with a higher affinity than IL-18Rα thus preventing IL-18 binding to IL-18 receptor.[13][14]IL-37 is another endogenous factor that suppresses the action of IL-18. IL-37 has high
homology with IL-18 and can bind to IL-18Rα, which then forms a complex with IL-18BP, thereby reducing the activity of IL-18.[15] Moreover, IL-37 binds to
single immunoglobulin IL-1 receptor related protein (SIGIRR), also known as IL-1R8 or TIR8, which forms a complex with IL-18Rα and induces an
anti-inflammatory response. The IL-37/IL-18Rα/IL-1R8 complex activates the
STAT3 signaling pathway, decreases
NF-κB and
AP-1 activation and reduces
IFNγ production. Thus, IL-37 and IL-18 have opposing roles and IL-37 can modulate pro-inflammatory effects of IL-18.[16][15]
Function
IL-18 belongs to the
IL-1 superfamily and is produced mainly by
macrophages but also by other cell types, stimulates various cell types and has pleiotropic functions. IL-18 is a proinflammatory cytokine that facilitates
type 1 responses. Together with
IL-12, it induces
cell-mediated immunity following infection with microbial products like
lipopolysaccharide (LPS). IL-18 in combination with IL12 acts on
CD4,
CD8 T cells and
NK cells to induce IFNγ production,
type II interferon that plays an important role in activating the macrophages or other cells. The combination of IL-18 and IL-12 has been shown to inhibit
IL-4 dependent
IgE and
IgG1 production and enhance IgG2a production in
B cells.[17] Importantly, without IL-12 or
IL-15, IL-18 does not induce IFNγ production, but plays an important role in the differentiation of naive T cells into
Th2 cells and stimulates
mast cells and
basophils to produce
IL-4,
IL-13, and chemical mediators such as
histamine.[18]
Clinical significance
Apart from its physiological role, IL-18 is also able to induce severe
inflammatory reactions, which suggests its role in certain inflammatory disorders such as
chronic inflammation and
autoimmune disorders.[19] High levels of IL18 have also been described in essential hypertensive subjects[20]
Endometrial
IL-18 receptor mRNA and the ratio of
IL-18 binding protein to interleukin 18 is significantly increased in
adenomyosis patients in comparison to normal people, indicating a role in its pathogenesis.[21]
IL-18 has been implicated as an inflammatory mediator of
Hashimoto's thyroiditis, the most common cause of autoimmune hypothyroidism. IL-18 is upregulated by
interferon-gamma.[22]
IL-18 has also been found to increase the
Alzheimer's disease-associated
amyloid-beta production in human neuron cells.[23]
IL-18 is also associated with urine protein excretion which means that it can be marker for assessing the progression of diabetic nephropathy.[24][25] This interleukin was also significantly elevated in patients with microalbuminuria and macroalbuminuria when it was compared with healthy people and patients with diabetes which have normoalbuminuria.[26]
IL-18 is involved in the neuroinflammatory response after intracerebral hemorrhage.[27]
The
single-nucleotide polymorphism (SNP) IL18 rs360719, a genetic variant of the Interleukin-18 (IL-18) gene, revealed a probable role in determining the susceptibility to
systemic lupus erythematosus and to be a possible "key factor in the expression of the IL18 gene."[19]
^Nolan KF, Greaves DR, Waldmann H (July 1998). "The human interleukin 18 gene IL18 maps to 11q22.2-q22.3, closely linked to the DRD2 gene locus and distinct from mapped IDDM loci". Genomics. 51 (1): 161–3.
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10.1006/geno.1998.5336.
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^Fabbi M, Carbotti G, Ferrini S (April 2015). "Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP". Journal of Leukocyte Biology. 97 (4): 665–75.
doi:
10.1189/jlb.5RU0714-360RR.
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^Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J (March 2019). "Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage". Prog. Neurobiol. 178: 101610.
doi:
10.1016/j.pneurobio.2019.03.003.
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Nakanishi K (February 2002). "[Regulation of Th1 and Th2 immune responses by IL-18]". Kekkaku. 77 (2): 87–93.
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Reddy P, Ferrara JL (June 2003). "Role of interleukin-18 in acute graft-vs-host disease". The Journal of Laboratory and Clinical Medicine. 141 (6): 365–71.
doi:
10.1016/S0022-2143(03)00028-3.
PMID12819633.
Kanai T, Uraushihara K, Totsuka T, Okazawa A, Hibi T, Oshima S, et al. (June 2003). "Macrophage-derived IL-18 targeting for the treatment of Crohn's disease". Current Drug Targets. Inflammation and Allergy. 2 (2): 131–6.
doi:
10.2174/1568010033484250.
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Matsui K, Tsutsui H, Nakanishi K (December 2003). "Pathophysiological roles for IL-18 in inflammatory arthritis". Expert Opinion on Therapeutic Targets. 7 (6): 701–24.
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