Interleukin 18 Explained

Interleukin-18 (IL-18), also known as interferon-gamma inducing factor is a protein which in humans is encoded by the IL18 gene.[1] [2] 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.[3] 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.[4] IL-18 can modulate both innate and adaptive immunity and its dysregulation can cause autoimmune or inflammatory diseases.[5] [6]

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.[7] 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.[8]

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.[9] [10] 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.[11] 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.[12] [11]

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.[13] 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.[14]

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.[15] High levels of IL18 have also been described in essential hypertensive subjects[16]

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.[17]

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.[18]

IL-18 has also been found to increase the Alzheimer's disease-associated amyloid-beta production in human neuron cells.[19]

IL-18 is also associated with urine protein excretion which means that it can be marker for assessing the progression of diabetic nephropathy.[20] [21] 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.[22]

IL-18 is involved in the neuroinflammatory response after intracerebral hemorrhage.[23]

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."

Further reading

Notes and References

  1. Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K . 6 . Cloning of a new cytokine that induces IFN-gamma production by T cells . Nature . 378 . 6552 . 88–91 . November 1995 . 7477296 . 10.1038/378088a0 . 1995Natur.378...88O . 4323405 .
  2. Nolan KF, Greaves DR, Waldmann H . 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 . July 1998 . 9693051 . 10.1006/geno.1998.5336 .
  3. Nakamura K, Okamura H, Wada M, Nagata K, Tamura T . Endotoxin-induced serum factor that stimulates gamma interferon production . Infection and Immunity . 57 . 2 . 590–5 . February 1989 . 10.1128/IAI.57.2.590-595.1989 . 2492265 . 313137 .
  4. Yasuda K, Nakanishi K, Tsutsui H . Interleukin-18 in Health and Disease . International Journal of Molecular Sciences . 20 . 3 . 649 . February 2019 . 30717382 . 6387150 . 10.3390/ijms20030649 . free .
  5. Baker KJ, Houston A, Brint E . IL-1 Family Members in Cancer; Two Sides to Every Story . en . Frontiers in Immunology . 10 . 1197 . 2019 . 31231372 . 6567883 . 10.3389/fimmu.2019.01197 . free .
  6. Fabbi M, Carbotti G, Ferrini S . Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP . Journal of Leukocyte Biology . 97 . 4 . 665–75 . April 2015 . 25548255 . 10.1189/jlb.5RU0714-360RR . 25636657 .
  7. Dinarello CA, Novick D, Puren AJ, Fantuzzi G, Shapiro L, Mühl H, Yoon DY, Reznikov LL, Kim SH, Rubinstein M . 6 . Overview of interleukin-18: more than an interferon-gamma inducing factor . Journal of Leukocyte Biology . 63 . 6 . 658–64 . June 1998 . 9620656 . 10.1002/jlb.63.6.658 . 9115114 . free .
  8. Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K, Kurimoto M, Tanimoto T, Flavell RA, Sato V, Harding MW, Livingston DJ, Su MS . 6 . Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme . Science . 275 . 5297 . 206–9 . January 1997 . 8999548 . 10.1126/science.275.5297.206 . 85955985 .
  9. Dinarello CA . Interleukin-18 . Methods . 19 . 1 . 121–32 . September 1999 . 10525448 . 10.1006/meth.1999.0837 .
  10. Kaplanski G . Interleukin-18: Biological properties and role in disease pathogenesis . Immunological Reviews . 281 . 1 . 138–153 . January 2018 . 29247988 . 10.1111/imr.12616 . 7165732 . free .
  11. Jia H, Liu J, Han B . Reviews of Interleukin-37: Functions, Receptors, and Roles in Diseases . BioMed Research International . 2018 . 3058640 . 2018 . 29805973 . 5899839 . 10.1155/2018/3058640 . free .
  12. Garlanda C, Anders HJ, Mantovani A . TIR8/SIGIRR: an IL-1R/TLR family member with regulatory functions in inflammation and T cell polarization . Trends in Immunology . 30 . 9 . 439–46 . September 2009 . 19699681 . 10.1016/j.it.2009.06.001 .
  13. Web site: Entrez Gene: IL18 interleukin 18 (interferon-gamma-inducing factor).
  14. Yasuda K, Nakanishi K, Tsutsui H . Interleukin-18 in Health and Disease . International Journal of Molecular Sciences . 20 . 3 . 649 . February 2019 . 30717382 . 10.3390/ijms20030649 . 6387150 . free .
  15. Book: Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus . 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 . . 18 . 19 . 1 October 2009 . 3739–3748 . 10.1093/hmg/ddp301 . . 0964-6906 . 441948395 . 19584085 . https://web.archive.org/web/20200830174120/https://academic.oup.com/hmg/article/18/19/3739/2385753?searchresult=1 . August 30, 2020 . live.
  16. Odewusi . OO . Osadolor . HB . Interleukin 10 And 18 Levels in Essential Hypertensives. . Journal of Applied Sciences and Environmental Management. . 2019 . 23 . 5 . 819–824. 10.4314/jasem.v23i5.7 . free .
  17. Huang HY, Yu HT, Chan SH, Lee CL, Wang HS, Soong YK . 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 . June 2010 . 19394601 . 10.1016/j.fertnstert.2009.01.132 . free .
  18. Liu Z, Wang H, Xiao W, Wang C, Liu G, Hong T . 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 . October 2010 . 20586818 . 3003839 . 10.1111/j.1365-2613.2010.00715.x .
  19. Sutinen EM, Pirttilä T, Anderson G, Salminen A, Ojala JO . Pro-inflammatory interleukin-18 increases Alzheimer's disease-associated amyloid-β production in human neuron-like cells . Journal of Neuroinflammation . 9 . 199 . August 2012 . 22898493 . 3458954 . 10.1186/1742-2094-9-199 . free .
  20. Liu F, Guo J, Zhang Q, Liu D, Wen L, Yang Y, Yang L, Liu Z . 6 . The Expression of Tristetraprolin and Its Relationship with Urinary Proteins in Patients with Diabetic Nephropathy . PLOS ONE . 10 . 10 . e0141471 . 2015-10-30 . 26517838 . 4627660 . 10.1371/journal.pone.0141471 . 2015PLoSO..1041471L . free .
  21. Nakamura A, Shikata K, Hiramatsu M, Nakatou T, Kitamura T, Wada J, Itoshima T, Makino H . 6 . Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes . Diabetes Care . 28 . 12 . 2890–5 . December 2005 . 16306550 . 10.2337/diacare.28.12.2890 . free .
  22. Zhang D, Ye S, Pan T . The role of serum and urinary biomarkers in the diagnosis of early diabetic nephropathy in patients with type 2 diabetes . PeerJ . 7 . e7079 . 2019-06-11 . 31218128 . 6568248 . 10.7717/peerj.7079 . free .
  23. Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J . Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage . Prog. Neurobiol. . 178 . 101610 . March 2019 . 30923023 . 10.1016/j.pneurobio.2019.03.003. 85495400 .

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