Cytokines usually contain the signal peptide which is necessary for theirextracellular release. However, the IL-18 protein, similar to otherIL-1 family members, lacks thissignal peptide.[11] Furthermore, similar toIL-1β, IL-18 is produced as a biologically inactiveprecursor. IL-18 gene encodes for a 193amino acids precursor, first synthesized as an inactive 24kDa precursor with no signal peptide, which accumulates in the cellcytoplasm. Similarly to IL-1β, the IL-18 precursor is processed intracellularly bycaspase 1 in theNLRP3inflammasome into its mature biologically active molecule of 18 kDa.[12]
IL-18receptor consists of theinducible component IL-18Rα, which binds the mature IL-18 with lowaffinity and theconstitutively expressedco-receptor IL-18Rβ. IL-18 binds theligand receptor IL-18Rα, inducing the recruitment of IL-18Rβ to form a high affinity complex, which signals through thetoll/interleukin-1 receptor (TIR) domain. This signaling domain recruits theMyD88adaptor protein that activatesproinflammatory programs andNF-κB pathway. The activity of IL-18 can be suppressed by extracellular interleukin 18 binding protein (IL-18BP) that bindssoluble 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 highhomology 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 tosingle immunoglobulin IL-1 receptor related protein (SIGIRR), also known as IL-1R8 or TIR8, which forms a complex with IL-18Rα and induces ananti-inflammatory response. The IL-37/IL-18Rα/IL-1R8 complex activates theSTAT3 signaling pathway, decreasesNF-κB andAP-1 activation and reducesIFNγ production. Thus, IL-37 and IL-18 have opposing roles and IL-37 can modulate pro-inflammatory effects of IL-18.[16][15]
IL-18 belongs to theIL-1 superfamily and is produced mainly bymacrophages but also by other cell types, stimulates various cell types and has pleiotropic functions. IL-18 is a proinflammatory cytokine that facilitatestype 1 responses. Together withIL-12, it inducescell-mediated immunity following infection with microbial products likelipopolysaccharide (LPS). IL-18 in combination with IL-12 acts onCD4,CD8 T cells andNK cells to induce IFNγ production, atype 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 inhibitIL-4 dependentIgE andIgG1 production and enhance IgG2a production inB cells.[17] Importantly, without IL-12 orIL-15, IL-18 does not induce IFNγ production, but plays an important role in the differentiation of naive T cells intoTh2 cells and stimulatesmast cells andbasophils to produceIL-4,IL-13, and chemical mediators such ashistamine.[18]
Apart from its physiological role, IL-18 is also able to induce severeinflammatory reactions, which suggests its role in certain inflammatory disorders such aschronic inflammation andautoimmune disorders.[19] High levels of IL18 have also been described in essential hypertensive subjects[20]
EndometrialIL-18 receptor mRNA and the ratio ofIL-18 binding protein to interleukin 18 is significantly increased inadenomyosis patients in comparison to normal people, indicating a role in its pathogenesis.[21]
IL-18 has been implicated as an inflammatory mediator ofHashimoto's thyroiditis, the most common cause of autoimmune hypothyroidism. IL-18 is upregulated byinterferon-gamma.[22]
IL-18 has also been found to increase theAlzheimer's disease-associatedamyloid-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]
Thesingle-nucleotide polymorphism (SNP) IL18 rs360719, a genetic variant of the Interleukin-18 (IL-18) gene, revealed a probable role in determining the susceptibility tosystemic 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):161–163.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):665–675.doi:10.1189/jlb.5RU0714-360RR.PMID25548255.S2CID25636657.
^Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, et al. (January 1997). "Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme".Science.275 (5297). New York, N.Y.:206–209.doi:10.1126/science.275.5297.206.PMID8999548.S2CID85955985.
^Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, et al. (March 2019). "Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage".Progress in Neurobiology.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). [Tuberculosis]: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):365–371.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):131–136.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):701–724.doi:10.1517/14728222.7.6.701.PMID14640907.S2CID25093203.
