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IL37
Identifiers
Aliases	IL37, FIL1, FIL1(ZETA), FIL1Z, IL-1F7, IL-1H, IL-1H4, IL-1RP1, IL-37, IL1F7, IL1H4, IL1RP1, interleukin 37, IL-23
External IDs	OMIM: 605510; HomoloGene: 105713; GeneCards: IL37; OMA:IL37 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) Band 2q14.1 Start 112,911,165 bp End 112,918,882 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in skin of arm skin of leg skin of thigh nipple skin of abdomen vena cava skin of hip subthalamic nucleus body of tongue ventral tegmental area n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytokine activity interleukin-1 receptor binding Cellular component extracellular region extracellular space nucleus cytoplasm intracellular membrane-bounded organelle nucleoplasm cytosol Biological process inflammatory response immune response cytokine-mediated signaling pathway regulation of signaling receptor activity cellular response to cytokine stimulus neutrophil chemotaxis positive regulation of interleukin-6 production positive regulation of I-kappaB kinase/NF-kappaB signaling positive regulation of JNK cascade cellular response to lipopolysaccharide Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 27178 n/a Ensembl ENSG00000125571 n/a UniProt Q9NZH6 n/a RefSeq (mRNA) NM_014439 NM_173202 NM_173203 NM_173204 NM_173205 n/a RefSeq (protein) NP_055254 NP_775294 NP_775295 NP_775296 NP_775297 n/a Location (UCSC) Chr 2: 112.91 – 112.92 Mb n/a PubMed search n/a
Wikidata
View/Edit Human

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.

Gene location and structure

The IL-37 gene is in the human located on the long chromosome arm of chromosome 2. There has not been found any homolog gene in mice genome. IL-37 undergoes alternative splicing with 5 different splice variants depending on which of the 6 possible exons are being expressed: IL-37a-e. IL-37b is the largest and most studied one; it shares the beta barrel structure that is spread within the interleukin-1 family.

Gene expression

IL-37a,b,c are being expressed in a variety of tissues - thymus, lung, colon, uterus, bone marrow. It is produced by immune cells, most of which are relevant to the immune inflammation response. Examples include natural killer cells, activated B lymphocytes, circulating blood monocytes, tissue macrophages, keratinocytes or epithelial cells.

Some IL-37 isoforms are tissue specific and have varying lengths depending on which exons are being expressed:

IL-37a is found in the brain. The isoform includes exons 3, 4, 5, and 6 and the isoform is 192 amino acids in length

IL-37b is found in the kidney, bone marrow, blood, skin, respiratory and urogenital tract. Exons 1, 2, 4, 5, and 6 are expressed and the isoform is 218 amino acids in length.

IL-37c is found in the heart, and contains exons 1, 2, 5, and 6 for a total amino acid length of 197.

IL-37d is found in the bone marrow and includes exons 1, 4, 5, and 6 for a total length of 197.

IL-37e is found in the testis and includes exons 1, 5, and 6 totaling 157 amino acids.

Function

The mechanism of IL-37 functions is still to be elucidated. Known functions of IL-37 include anti-inflammatory effects, tumor suppression, and antimicrobial responses. IL-37 acts intracellulary and extracellulary, classifying the cytokine as dual-function.

IL-37 synthesis

IL-37, similar to other members of the interleukin-1 family, is synthesized by blood monocytes in a precursor form and secreted into the cytoplasm in response to inflammatory signaling. Examples of relevant inflammatory signals include TLR agonists, IL-1β, or TGF-β. Full maturation requires cleavage by Caspase-1.

Immune system inhibition

IL-37 is known to have immunosuppression properties through two different binding mechanisms:

Interaction with IL-18 cell surface receptors - Intracellular IL-37 can be released from cells following necrosis or apoptosis. IL-37 has two similar amino acid residues with IL-18, and thus extracellular IL-37 can interact with IL-18 receptor (IL-18R) and co-receptor IL-1 receptor 8 (IL-1R8). The affinity of IL-37b to IL-18R alpha subunit is much lower compared to IL-18. IL-37b interacts with IL-18 binding protein (IL-18BP), that is an antagonist of IL-18. The binding of IL-37b enhances the IL-18BP functions and can upregulate anti-inflammatory signals.

Binding to SMAD3 receptor - Mature intracellular IL-37 can form functional complexes with phosphorylated or unphosphorylated Smad3,which can be transported to the cell nucleus. Nucleus IL-37 can have a direct inhibition function on the expression of pro-inflammatory cytokine gene transcription. Affected cytokines include IL-1β, IFN-γ, IL-6, and TNF-α.

Tumor-controlled expression

IL-37 functions are active at low IL-37 concentrations. Higher concentrations leads to inactivation via dimer formation. Experiments also show that certain cancer strains correspond to changes in IL-37 expression levels. Breast cancer and ovarian cancer are associated with elevated expression of IL-37. Colon cancer, lung cancer, Multiple Myeloma, and Hepatoma Carcinoma were correlated with decreased expression of IL-37 expression in affected areas.

See also

• Interleukin-1 family
• Interleukin 18
• Interleukin 18 receptor
• Interleukin 18 binding protein
• Inflammation
• Carcinogenesis

References

1. ^ GRCh38: Ensembl release 89: ENSG00000125571 – Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. ^ Wang L, Quan Y, Yue Y, Heng X, Che F (April 2018). "Interleukin-37: A crucial cytokine with multiple roles in disease and potentially clinical therapy". Oncology Letters. 15 (4): 4711–4719. doi:10.3892/ol.2018.7982. PMC 5840652. PMID 29552110.
4. ^ Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA (November 2010). "IL-37 is a fundamental inhibitor of innate immunity". Nature Immunology. 11 (11): 1014–1022. doi:10.1038/ni.1944. PMC 3537119. PMID 20935647.
5. ^ Mei Y, Liu H (April 2019). "IL-37: An anti-inflammatory cytokine with antitumor functions". Cancer Reports. 2 (2): e1151. doi:10.1002/cnr2.1151. PMC 7941439. PMID 32935478.
6. ^ Bello RO, Chin VK, Abd Rachman Isnadi MF, Abd Majid R, Atmadini Abdullah M, Lee TY, et al. (April 2018). "The Role, Involvement and Function(s) of Interleukin-35 and Interleukin-37 in Disease Pathogenesis". International Journal of Molecular Sciences. 19 (4): 1149. doi:10.3390/ijms19041149. PMC 5979316. PMID 29641433.
7. ^ Pan Y, Wen X, Hao D, Wang Y, Wang L, He G, Jiang X (February 2020). "The role of IL-37 in skin and connective tissue diseases". Biomedicine & Pharmacotherapy. 122: 109705. doi:10.1016/j.biopha.2019.109705. PMID 31918276.
8. Jia H, Liu J, Han B (2018-04-01). "Reviews of Interleukin-37: Functions, Receptors, and Roles in Diseases". BioMed Research International. 2018: 3058640. doi:10.1155/2018/3058640. PMC 5899839. PMID 29805973.

Further reading

• Nold-Petry CA, Lo CY, Rudloff I, Elgass KD, Li S, Gantier MP, et al. (April 2015). "IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction". Nature Immunology. 16 (4): 354–365. doi:10.1038/ni.3103. PMID 25729923. S2CID 24578661.
• Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA (November 2010). "IL-37 is a fundamental inhibitor of innate immunity". Nature Immunology. 11 (11): 1014–1022. doi:10.1038/ni.1944. PMC 3537119. PMID 20935647.
• Nicklin MJ, Weith A, Duff GW (January 1994). "A physical map of the region encompassing the human interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist genes". Genomics. 19 (2): 382–384. doi:10.1006/geno.1994.1076. PMID 8188271.
• Nothwang HG, Strahm B, Denich D, Kübler M, Schwabe J, Gingrich JC, et al. (May 1997). "Molecular cloning of the interleukin-1 gene cluster: construction of an integrated YAC/PAC contig and a partial transcriptional map in the region of chromosome 2q13". Genomics. 41 (3): 370–378. doi:10.1006/geno.1997.4654. PMID 9169134.
• Kumar S, McDonnell PC, Lehr R, Tierney L, Tzimas MN, Griswold DE, et al. (April 2000). "Identification and initial characterization of four novel members of the interleukin-1 family". The Journal of Biological Chemistry. 275 (14): 10308–10314. doi:10.1074/jbc.275.14.10308. PMID 10744718.
• Busfield SJ, Comrack CA, Yu G, Chickering TW, Smutko JS, Zhou H, et al. (June 2000). "Identification and gene organization of three novel members of the IL-1 family on human chromosome 2". Genomics. 66 (2): 213–216. doi:10.1006/geno.2000.6184. PMID 10860666.
• Barton JL, Herbst R, Bosisio D, Higgins L, Nicklin MJ (November 2000). "A tissue specific IL-1 receptor antagonist homolog from the IL-1 cluster lacks IL-1, IL-1ra, IL-18 and IL-18 antagonist activities". European Journal of Immunology. 30 (11): 3299–3308. doi:10.1002/1521-4141(200011)30:11<3299::AID-IMMU3299>3.0.CO;2-S. PMID 11093146.
• Pan G, Risser P, Mao W, Baldwin DT, Zhong AW, Filvaroff E, et al. (January 2001). "IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp". Cytokine. 13 (1): 1–7. doi:10.1006/cyto.2000.0799. PMID 11145836.
• Lin H, Ho AS, Haley-Vicente D, Zhang J, Bernal-Fussell J, Pace AM, et al. (June 2001). "Cloning and characterization of IL-1HY2, a novel interleukin-1 family member". The Journal of Biological Chemistry. 276 (23): 20597–20602. doi:10.1074/jbc.M010095200. PMID 11278614.
• Debets R, Timans JC, Homey B, Zurawski S, Sana TR, Lo S, et al. (August 2001). "Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2". Journal of Immunology. 167 (3): 1440–1446. doi:10.4049/jimmunol.167.3.1440. PMID 11466363. S2CID 85986577.
• Sims JE, Nicklin MJ, Bazan JF, Barton JL, Busfield SJ, Ford JE, et al. (October 2001). "A new nomenclature for IL-1-family genes". Trends in Immunology. 22 (10): 536–537. doi:10.1016/S1471-4906(01)02040-3. PMID 11574262.
• Nicklin MJ, Barton JL, Nguyen M, FitzGerald MG, Duff GW, Kornman K (May 2002). "A sequence-based map of the nine genes of the human interleukin-1 cluster". Genomics. 79 (5): 718–725. doi:10.1006/geno.2002.6751. PMID 11991722.
• Taylor SL, Renshaw BR, Garka KE, Smith DE, Sims JE (May 2002). "Genomic organization of the interleukin-1 locus". Genomics. 79 (5): 726–733. doi:10.1006/geno.2002.6752. PMID 11991723.
• Kumar S, Hanning CR, Brigham-Burke MR, Rieman DJ, Lehr R, Khandekar S, et al. (April 2002). "Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production". Cytokine. 18 (2): 61–71. doi:10.1006/cyto.2002.0873. PMID 12096920.
• Bufler P, Azam T, Gamboni-Robertson F, Reznikov LL, Kumar S, Dinarello CA, Kim SH (October 2002). "A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity". Proceedings of the National Academy of Sciences of the United States of America. 99 (21): 13723–13728. Bibcode:2002PNAS...9913723B. doi:10.1073/pnas.212519099. PMC 129755. PMID 12381835.
• Grimsby S, Jaensson H, Dubrovska A, Lomnytska M, Hellman U, Souchelnytskyi S (November 2004). "Proteomics-based identification of proteins interacting with Smad3: SREBP-2 forms a complex with Smad3 and inhibits its transcriptional activity". FEBS Letters. 577 (1–2): 93–100. doi:10.1016/j.febslet.2004.09.069. PMID 15527767. S2CID 82568.

External links

• Overview of all the structural information available in the PDB for UniProt: Q9NZH6 (Interleukin-37) at the PDBe-KB.

• Genes on human chromosome 2