Interleukin 18

Last updated
IL18
IL18 Solution Structure.rsh.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IL18 , IGIF, IL-18, IL-1g, IL1F4, interleukin 18
External IDs OMIM: 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 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, 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, 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] High levels of IL18 have alo been described in essential hypertensive subjects [20]

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. [21]

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. [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 what 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]

Related Research Articles

<span class="mw-page-title-main">Cytokine</span> Broad and loose category of small proteins important in cell signaling

Cytokines are a broad and loose category of small proteins important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

Interleukins (ILs) are a group of cytokines that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related proteins.

<span class="mw-page-title-main">Interleukin 10</span> Anti-inflammatory cytokine

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

<span class="mw-page-title-main">Interleukin 12</span> Interleukin

Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, helper T cells and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.

<span class="mw-page-title-main">Interleukin 4</span> Mammalian protein found in Mus musculus

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.

<span class="mw-page-title-main">Interleukin 13</span> Protein and coding gene in humans

Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.

<span class="mw-page-title-main">Interleukin 15</span> Cytokine with structural similarity to Interleukin-2

Interleukin-15 (IL-15) is a protein that in humans is encoded by the IL15 gene. IL-15 is an inflammatory cytokine with structural similarity to Interleukin-2 (IL-2). Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD122) and the common gamma chain. IL-15 is secreted by mononuclear phagocytes following infection by virus(es). This cytokine induces the proliferation of natural killer cells, i.e. cells of the innate immune system whose principal role is to kill virally infected cells.

<span class="mw-page-title-main">Interleukin 29</span> Protein-coding gene in the species Homo sapiens

Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.

<span class="mw-page-title-main">Interleukin 26</span>

Interleukin-26 (IL-26) is a protein that in humans is encoded by the IL26 gene.

<span class="mw-page-title-main">Interleukin 22</span> Protein, encoded in humans by IL22 gene

Interleukin-22 (IL-22) is protein that in humans is encoded by the IL22 gene.

Type II cytokine receptors, also commonly known as class II cytokine receptors, are transmembrane proteins that are expressed on the surface of certain cells. They bind and respond to a select group of cytokines including interferon type I, interferon type II, interferon type III. and members of the interleukin-10 family These receptors are characterized by the lack of a WSXWS motif which differentiates them from type I cytokine receptors.

<span class="mw-page-title-main">Tyrosine kinase 2</span> Enzyme and coding gene in humans

Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.

<span class="mw-page-title-main">STAT4</span> Protein-coding gene in the species Homo sapiens

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient. STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12. There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma production downstream.

<span class="mw-page-title-main">IL18BP</span> Protein-coding gene in the species Homo sapiens

Interleukin-18-binding protein is a protein that in humans is encoded by the IL18BP gene.

<span class="mw-page-title-main">Interleukin 37</span> Protein-coding gene in the species Homo sapiens

Interleukin 37 (IL-37), also known as Interleukin-1 family member 7 (IL-1F7), is an anti-inflammatory cytokine important for the downregulation of pro-inflammatory cytokine production as well as the suppression of tumor cell growth.

Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.

<span class="mw-page-title-main">IL18R1</span> Protein-coding gene in the species Homo sapiens

The interleukin-18 receptor 1 (IL-18R1) is an interleukin receptor of the immunoglobulin superfamily. IL18R1 is its human gene. IL18R1 is also known as CDw218a.

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000150782 - Ensembl, May 2017
  2. 1 2 3 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.
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  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.
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  15. 1 2 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. 1 2 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.

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