Interleukin 18

For the Soviet four-engined turboprop airliner dubbed "Il-18", see Ilyushin Il-18.

IL18
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1J0S, 2VXT, 3F62, 4EEE, 4EKX, 4HJJ, 3WO2, 3WO3, 3WO4, 4R6U, 4XFS, 4XFT, 4XFU
Identifiers
Aliases	IL18, IGIF, IL-18, IL-1g, IL1F4, interleukin 18
External IDs	OMIM: 600953; MGI: 107936; HomoloGene: 1200; GeneCards: IL18; OMA:IL18 - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q23.1 Start 112,143,253 bp[1] End 112,164,096 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 A5.3|9 27.75 cM Start 50,466,127 bp[2] End 50,493,140 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in skin of abdomen skin of leg rectum skin of thigh gallbladder mucosa of transverse colon olfactory zone of nasal mucosa germinal epithelium human penis oral cavity Top expressed in epithelium of stomach pyloric antrum mucous cell of stomach left colon skin of external ear esophagus duodenum jejunum spleen lip More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding cytokine activity interleukin-18 receptor binding Cellular component cytosol extracellular region extracellular space Biological process positive regulation of inflammatory response cell-cell signaling cellular response to organic cyclic compound type 2 immune response MAPK cascade positive regulation of natural killer cell proliferation sleep regulation of cell adhesion positive regulation of NK T cell proliferation positive regulation of granulocyte macrophage colony-stimulating factor production positive regulation of tissue remodeling angiogenesis T-helper 1 type immune response positive regulation of interleukin-17 production inflammatory response lipopolysaccharide-mediated signaling pathway positive regulation of activated T cell proliferation positive regulation of protein kinase B signaling positive regulation of phosphatidylinositol 3-kinase signaling positive regulation of smooth muscle cell proliferation activation of protein kinase B activity positive regulation of transcription by RNA polymerase II positive regulation of tyrosine phosphorylation of STAT protein positive regulation of gene expression positive regulation of macrophage derived foam cell differentiation natural killer cell activation positive regulation of interferon-gamma production cholesterol homeostasis positive regulation of T-helper 2 cell differentiation negative regulation of myoblast differentiation triglyceride homeostasis cell population proliferation regulation of signaling receptor activity interleukin-6 production T-helper 1 cell cytokine production neutrophil activation natural killer cell mediated cytotoxicity cytokine-mediated signaling pathway interleukin-18-mediated signaling pathway positive regulation of NIK/NF-kappaB signaling immune response positive regulation of NF-kappaB transcription factor activity positive regulation of T-helper 1 cell cytokine production positive regulation of cold-induced thermogenesis positive regulation of neuroinflammatory response signal transduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 9: 50.47 – 50.49 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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, and 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]

Processing

Cytokines usually contain the signal peptide which is necessary for their extracellular release. In this case, the 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 the 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 the 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 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]

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.^{[permanent dead link‍]}
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. Vol. 18. Oxford University Press. 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. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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

• 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. PMID 11894141. S2CID 34752902.
• Nakanishi K (February 2002). "[Regulation of Th1 and Th2 immune responses by IL-18]". Kekkaku. 77 (2): 87–93. PMID 11905033.
• 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. PMID 12819633.
• 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. PMID 14561165.
• 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. PMID 14640907. S2CID 25093203.
• 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. PMID 17075246.
• 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. PMID 17586702. S2CID 26910667.

External links

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