Interleukin-18(IL-18), also known asinterferon-gamma inducing factoris aproteinwhich in humans is encoded by theIL18gene.[5][6]The protein encoded by this gene is aproinflammatory cytokine.Many cell types, bothhematopoietic cellsand non-hematopoietic cells, have the potential to produce IL-18. It was first described in 1989 as a factor that inducedinterferon-γ(IFN-γ) production in mouse spleen cells.[7]Originally, IL-18 production was recognized inKupffer cells,and liver-resident macrophages. However, IL-18 is constitutively expressed in non-hematopoietic cells, such asintestinal epithelial cells,keratinocytes,andendothelial cells.[8]IL-18 can modulate bothinnateandadaptiveimmunity and its dysregulation can causeautoimmuneorinflammatory diseases.[9][10]
Processing
editCytokinesusually contain the signal peptide which is necessary for theirextracellularrelease. In this case, theIL18gene,similar to otherIL-1 familymembers, lacks thissignal peptide.[11]Furthermore, similar toIL-1β,IL-18 is produced as a biologically inactiveprecursor.IL-18 gene encodes for a 193amino acidsprecursor, first synthesized as an inactive 24kDaprecursor with no signal peptide, which accumulates in the cellcytoplasm.Similarly to IL-1β, the IL-18 precursor is processed intracellularly bycaspase 1in theNLRP3inflammasomeinto its mature biologically active molecule of 18 kDa.[12]
Receptor and signaling
editIL-18receptorconsists of theinduciblecomponent IL-18Rα, which binds the mature IL-18 with lowaffinityand theconstitutively expressedco-receptorIL-18Rβ. IL-18 binds theligandreceptor 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 proteinthat activatesproinflammatoryprograms andNF-κB pathway.The activity of IL-18 can be suppressed by extracellular interleukin 18 binding protein (IL-18BP) that bindssolubleIL-18 with a higher affinity than IL-18Rα thus preventing IL-18 binding to IL-18 receptor.[13][14]IL-37is another endogenous factor that suppresses the action of IL-18. IL-37 has highhomologywith 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-inflammatoryresponse. The IL-37/IL-18Rα/IL-1R8 complex activates theSTAT3signaling pathway, decreasesNF-κBandAP-1activation and reducesIFNγproduction. Thus, IL-37 and IL-18 have opposing roles and IL-37 can modulate pro-inflammatory effects of IL-18.[16][15]
Function
editIL-18 belongs to theIL-1 superfamilyand is produced mainly bymacrophagesbut 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 immunityfollowing infection with microbial products likelipopolysaccharide(LPS). IL-18 in combination with IL12 acts onCD4,CD8T cells andNK cellsto induce IFNγ production,type II interferonthat plays an important role in activating the macrophages or other cells. The combination of IL-18 and IL-12 has been shown to inhibitIL-4dependentIgEandIgG1production 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 cellsand stimulatesmast cellsandbasophilsto produceIL-4,IL-13,and chemical mediators such ashistamine.[18]
Clinical significance
editApart from its physiological role, IL-18 is also able to induce severeinflammatory reactions,which suggests its role in certain inflammatory disorders such aschronic inflammationandautoimmune disorders.[19]High levels of IL18 have also been described in essential hypertensive subjects[20]
EndometrialIL-18 receptormRNA and the ratio ofIL-18 binding proteinto interleukin 18 is significantly increased inadenomyosispatients 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'sdisease-associatedamyloid-betaproduction 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 erythematosusand to be a possible "key factor in the expression of the IL18 gene."[19]
References
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- ^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): 206–9.doi:10.1126/science.275.5297.206.PMID8999548.S2CID85955985.
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- ^abJia H, Liu J, Han B (2018)."Reviews of Interleukin-37: Functions, Receptors, and Roles in Diseases".BioMed Research International.2018:3058640.doi:10.1155/2018/3058640.PMC5899839.PMID29805973.
- ^Garlanda C, Anders HJ, Mantovani A (September 2009)."TIR8/SIGIRR: an IL-1R/TLR family member with regulatory functions in inflammation and T cell polarization".Trends in Immunology.30(9): 439–46.doi:10.1016/j.it.2009.06.001.PMID19699681.[permanent dead link]
- ^"Entrez Gene: IL18 interleukin 18 (interferon-gamma-inducing factor)".
- ^Yasuda K, Nakanishi K, Tsutsui H (February 2019)."Interleukin-18 in Health and Disease".International Journal of Molecular Sciences.20(3): 649.doi:10.3390/ijms20030649.PMC6387150.PMID30717382.
- ^abE. Sánchez, R. J. Palomino-Morales, N. Ortego-Centeno, J. Jiménez-Alonso, M. A. González-Gay, M. A. López-Nevot, J. Sánchez-Román, E. de Ramón, M. F. González-Escribano, B. A. Pons-Estel (1 October 2009).Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus.Vol. 18.Oxford University Press.pp. 3739–3748.doi:10.1093/hmg/ddp301.ISSN0964-6906.OCLC441948395.PMID19584085.Archivedfrom the original on August 30, 2020.
{{cite book}}:|journal=ignored (help) - ^Odewusi OO, Osadolor HB (2019)."Interleukin 10 And 18 Levels in Essential Hypertensives".Journal of Applied Sciences and Environmental Management.23(5): 819–824.doi:10.4314/jasem.v23i5.7.
- ^Huang HY, Yu HT, Chan SH, Lee CL, Wang HS, Soong YK (June 2010)."Eutopic endometrial interleukin-18 system mRNA and protein expression at the level of endometrial-myometrial interface in adenomyosis patients".Fertility and Sterility.94(1): 33–9.doi:10.1016/j.fertnstert.2009.01.132.PMID19394601.
- ^Liu Z, Wang H, Xiao W, Wang C, Liu G, Hong T (October 2010)."Thyrocyte interleukin-18 expression is up-regulated by interferon-γ and may contribute to thyroid destruction in Hashimoto's thyroiditis".International Journal of Experimental Pathology.91(5): 420–5.doi:10.1111/j.1365-2613.2010.00715.x.PMC3003839.PMID20586818.
- ^Sutinen EM, Pirttilä T, Anderson G, Salminen A, Ojala JO (August 2012)."Pro-inflammatory interleukin-18 increases Alzheimer's disease-associated amyloid-β production in human neuron-like cells".Journal of Neuroinflammation.9:199.doi:10.1186/1742-2094-9-199.PMC3458954.PMID22898493.
- ^Liu F, Guo J, Zhang Q, Liu D, Wen L, Yang Y, et al. (2015-10-30)."The Expression of Tristetraprolin and Its Relationship with Urinary Proteins in Patients with Diabetic Nephropathy".PLOS ONE.10(10): e0141471.Bibcode:2015PLoSO..1041471L.doi:10.1371/journal.pone.0141471.PMC4627660.PMID26517838.
- ^Nakamura A, Shikata K, Hiramatsu M, Nakatou T, Kitamura T, Wada J, et al. (December 2005)."Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes".Diabetes Care.28(12): 2890–5.doi:10.2337/diacare.28.12.2890.PMID16306550.
- ^Zhang D, Ye S, Pan T (2019-06-11)."The role of serum and urinary biomarkers in the diagnosis of early diabetic nephropathy in patients with type 2 diabetes".PeerJ.7:e7079.doi:10.7717/peerj.7079.PMC6568248.PMID31218128.
- ^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.
Further reading
edit- Biet F, Locht C, Kremer L (March 2002)."Immunoregulatory functions of interleukin 18 and its role in defense against bacterial pathogens".Journal of Molecular Medicine.80(3): 147–62.doi:10.1007/s00109-001-0307-1.PMID11894141.S2CID34752902.
- 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.
- Yoshimoto T, Nakanishi K (June 2006)."Roles of IL-18 in basophils and mast cells".Allergology International.55(2): 105–13.doi:10.2332/allergolint.55.105.PMID17075246.
- Orozco A, Gemmell E, Bickel M, Seymour GJ (July 2007). "Interleukin 18 and periodontal disease".Journal of Dental Research.86(7): 586–93.doi:10.1177/154405910708600702.PMID17586702.S2CID26910667.