Cytokines usually contain the signal peptide which is necessary for their extracellular release. However, the IL-18 protein, 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 IL-12 acts on CD4, CD8 T cells and NK cells to induce IFNγ production, a type II interferon that plays an important role in activating macrophages and 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. doi:10.1006/geno.1998.5336. PMID9693051.
^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. PMID25548255. S2CID25636657.
^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. PMID30923023. S2CID85495400.
Nakanishi K (February 2002). "[Regulation of Th1 and Th2 immune responses by IL-18]". Kekkaku. 77 (2): 87–93. PMID11905033.
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. PMID14561165.
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. doi:10.1517/14728222.7.6.701. PMID14640907. S2CID25093203.
