Interleukin 18

Interleukin-18 (IL-18), also known as interferon-gamma inducing factor is a protein which in humans is encoded by the IL18 gene.[5][6] The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and non-hematopoietic cells, have the potential to produce IL-18. It was first described in 1989 as a factor that induced interferon-γ (IFN-γ) production in mouse spleen cells.[7] Originally, IL-18 production was recognized in Kupffer cells, liver-resident macrophages. However, IL-18 is constitutively expressed in non-hematopoietic cells, such as intestinal epithelial cells, keratinocytes, and endothelial cells.[8] IL-18 can modulate both innate and adaptive immunity and its dysregulation can cause autoimmune or inflammatory diseases.[9][10]

For the Soviet four-engined turboprop airliner dubbed "Il-18", see Ilyushin Il-18.
IL18
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIL18, IGIF, IL-18, IL-1g, IL1F4, interleukin 18
External IDsOMIM: 600953 MGI: 107936 HomoloGene: 1200 GeneCards: IL18
Orthologs
SpeciesHumanMouse
Entrez

3606

16173

Ensembl

ENSG00000150782

ENSMUSG00000039217

UniProt

Q14116

P70380

RefSeq (mRNA)

NM_001243211
NM_001562
NM_001386420

NM_008360
NM_001357221
NM_001357222

RefSeq (protein)

NP_001230140
NP_001553
NP_001230140.1

NP_032386
NP_001344150
NP_001344151

Location (UCSC)Chr 11: 112.14 – 112.16 MbChr 9: 50.47 – 50.49 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Processing

Cytokines usually contain the signal peptide which is necessary for their extracellular release. In this case, IL18 gene, 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 cell cytoplasm. Similarly to IL-1β, the IL-18 precursor is processed intracellularly by caspase 1 in the NLRP3 inflammasome 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 expressed co-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 MyD88 adaptor 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 prevents 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 reduces 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 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 this 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 the chronic inflammation and the autoimmune disorders.[19]

Endometrial IL-18 receptor mRNA and the ratio of IL-18 binding protein to interleukin 18 are significantly increased in adenomyosis patients in comparison to normal people, indicating a role in its pathogenesis.[20]

IL-18 has been implicated as an inflammatory mediator of Hashimoto's thyroiditis, the most common cause of autoimmune hypothyroidism. IL-18 is up regulated by interferon-gamma.[21]

IL-18 has also been found to increase the Alzheimer's disease-associated amyloid-beta production in human neuron cells.[22]

IL-18 is also associated with urine protein excretion what means that it can be marker for assessing the progression of diabetic nephropathy.[23][24] 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.[25]

IL-18 is involved in the neuroinflammatory response after intracerebral hemorrhage.[26]

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]

References
  1. GRCh38: Ensembl release 89: ENSG00000150782 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000039217 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, et al. (November 1995). "Cloning of a new cytokine that induces IFN-gamma production by T cells". Nature. 378 (6552): 88–91. Bibcode:1995Natur.378...88O. doi:10.1038/378088a0. PMID 7477296. S2CID 4323405.
  6. 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. PMID 9693051.
  7. Nakamura K, Okamura H, Wada M, Nagata K, Tamura T (February 1989). "Endotoxin-induced serum factor that stimulates gamma interferon production". Infection and Immunity. 57 (2): 590–5. doi:10.1128/IAI.57.2.590-595.1989. PMC 313137. PMID 2492265.
  8. 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. PMC 6387150. PMID 30717382.
  9. Baker KJ, Houston A, Brint E (2019). "IL-1 Family Members in Cancer; Two Sides to Every Story". Frontiers in Immunology. 10: 1197. doi:10.3389/fimmu.2019.01197. PMC 6567883. PMID 31231372.
  10. 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. PMID 25548255. S2CID 25636657.
  11. Dinarello CA, Novick D, Puren AJ, Fantuzzi G, Shapiro L, Mühl H, et al. (June 1998). "Overview of interleukin-18: more than an interferon-gamma inducing factor". Journal of Leukocyte Biology. 63 (6): 658–64. doi:10.1002/jlb.63.6.658. PMID 9620656. S2CID 9115114.
  12. 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. PMID 8999548. S2CID 85955985.
  13. Dinarello CA (September 1999). "Interleukin-18". Methods. 19 (1): 121–32. doi:10.1006/meth.1999.0837. PMID 10525448.
  14. Kaplanski G (January 2018). "Interleukin-18: Biological properties and role in disease pathogenesis". Immunological Reviews. 281 (1): 138–153. doi:10.1111/imr.12616. PMC 7165732. PMID 29247988.
  15. Jia 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. PMC 5899839. PMID 29805973.
  16. 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. PMID 19699681.
  17. "Entrez Gene: IL18 interleukin 18 (interferon-gamma-inducing factor)".
  18. 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. PMC 6387150. PMID 30717382.
  19. E. 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. pp. 3739–3748. doi:10.1093/hmg/ddp301. ISSN 0964-6906. OCLC 441948395. PMID 19584085. Archived from the original on August 30, 2020. {{cite book}}: |journal= ignored (help)
  20. 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. PMID 19394601.
  21. 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. PMC 3003839. PMID 20586818.
  22. 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. PMC 3458954. PMID 22898493.
  23. 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. PMC 4627660. PMID 26517838.
  24. 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. PMID 16306550.
  25. 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. PMC 6568248. PMID 31218128.
  26. 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. PMID 30923023. S2CID 85495400.

Further reading
  • Overview of all the structural information available in the PDB for UniProt: Q14116 (Interleukin-18) at the PDBe-KB.
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