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.[3]

IL37
Identifiers
AliasesIL37, FIL1, FIL1(ZETA), FIL1Z, IL-1F7, IL-1H, IL-1H4, IL-1RP1, IL-37, IL1F7, IL1H4, IL1RP1, interleukin 37, IL-23
External IDsOMIM: 605510; HomoloGene: 105713; GeneCards: IL37; OMA:IL37 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Gene location and structure

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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.[4] IL-37 undergoes alternative splicing with 5 different splice variants depending on which of the 6 possible exons are being expressed: IL-37a-e.[5] IL-37b is the largest and most studied one; it shares the beta barrel structure that is spread within the interleukin-1 family.[3]

Gene expression

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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.[3][6]

Function

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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.[3]

IL-37 synthesis

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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.[5] Full maturation requires cleavage by Caspase-1.[7]

Immune system inhibition

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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.[6] 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.[4][7]

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.[5][8][6]

Tumor-controlled expression

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IL-37 functions are active at low IL-37 concentrations. Higher concentrations leads to inactivation via dimer formation.[6] 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.[5]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000125571Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ a b c d 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 29552110.4711-4719&rft.date=2018-04&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840652#id-name=PMC&rft_id=info:pmid/29552110&rft_id=info:doi/10.3892/ol.2018.7982&rft.aulast=Wang&rft.aufirst=L&rft.au=Quan, Y&rft.au=Yue, Y&rft.au=Heng, X&rft.au=Che, F&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840652&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  4. ^ a b 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 20935647.1014-1022&rft.date=2010-11&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537119#id-name=PMC&rft_id=info:pmid/20935647&rft_id=info:doi/10.1038/ni.1944&rft.aulast=Nold&rft.aufirst=MF&rft.au=Nold-Petry, CA&rft.au=Zepp, JA&rft.au=Palmer, BE&rft.au=Bufler, P&rft.au=Dinarello, CA&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537119&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  5. ^ a b c d 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. ^ a b c d 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. ^ a b 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

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  • 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 24578661.354-365&rft.date=2015-04&rft_id=https://api.semanticscholar.org/CorpusID:24578661#id-name=S2CID&rft_id=info:pmid/25729923&rft_id=info:doi/10.1038/ni.3103&rft.aulast=Nold-Petry&rft.aufirst=CA&rft.au=Lo, CY&rft.au=Rudloff, I&rft.au=Elgass, KD&rft.au=Li, S&rft.au=Gantier, MP&rft.au=Lotz-Havla, AS&rft.au=Gersting, SW&rft.au=Cho, SX&rft.au=Lao, JC&rft.au=Ellisdon, AM&rft.au=Rotter, B&rft.au=Azam, T&rft.au=Mangan, NE&rft.au=Rossello, FJ&rft.au=Whisstock, JC&rft.au=Bufler, P&rft.au=Garlanda, C&rft.au=Mantovani, A&rft.au=Dinarello, CA&rft.au=Nold, MF&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 20935647.1014-1022&rft.date=2010-11&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537119#id-name=PMC&rft_id=info:pmid/20935647&rft_id=info:doi/10.1038/ni.1944&rft.aulast=Nold&rft.aufirst=MF&rft.au=Nold-Petry, CA&rft.au=Zepp, JA&rft.au=Palmer, BE&rft.au=Bufler, P&rft.au=Dinarello, CA&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537119&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 8188271.382-384&rft.date=1994-01&rft_id=info:doi/10.1006/geno.1994.1076&rft_id=info:pmid/8188271&rft.aulast=Nicklin&rft.aufirst=MJ&rft.au=Weith, A&rft.au=Duff, GW&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 9169134.370-378&rft.date=1997-05&rft_id=info:doi/10.1006/geno.1997.4654&rft_id=info:pmid/9169134&rft.aulast=Nothwang&rft.aufirst=HG&rft.au=Strahm, B&rft.au=Denich, D&rft.au=Kübler, M&rft.au=Schwabe, J&rft.au=Gingrich, JC&rft.au=Jauch, A&rft.au=Cox, A&rft.au=Nicklin, MJ&rft.au=Kurnit, DM&rft.au=Hildebrandt, F&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 10744718.10308-10314&rft.date=2000-04&rft_id=info:doi/10.1074/jbc.275.14.10308&rft_id=info:pmid/10744718&rft.aulast=Kumar&rft.aufirst=S&rft.au=McDonnell, PC&rft.au=Lehr, R&rft.au=Tierney, L&rft.au=Tzimas, MN&rft.au=Griswold, DE&rft.au=Capper, EA&rft.au=Tal-Singer, R&rft.au=Wells, GI&rft.au=Doyle, ML&rft.au=Young, PR&rft_id=https://doi.org/10.1074%2Fjbc.275.14.10308&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 10860666.213-216&rft.date=2000-06&rft_id=info:doi/10.1006/geno.2000.6184&rft_id=info:pmid/10860666&rft.aulast=Busfield&rft.aufirst=SJ&rft.au=Comrack, CA&rft.au=Yu, G&rft.au=Chickering, TW&rft.au=Smutko, JS&rft.au=Zhou, H&rft.au=Leiby, KR&rft.au=Holmgren, LM&rft.au=Gearing, DP&rft.au=Pan, Y&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 11093146.3299-3308&rft.date=2000-11&rft_id=info:doi/10.1002/1521-4141(200011)30:11<3299::AID-IMMU3299>3.0.CO;2-S&rft_id=info:pmid/11093146&rft.aulast=Barton&rft.aufirst=JL&rft.au=Herbst, R&rft.au=Bosisio, D&rft.au=Higgins, L&rft.au=Nicklin, MJ&rft_id=https://doi.org/10.1002%2F1521-4141%28200011%2930%3A11%3C3299%3A%3AAID-IMMU3299%3E3.0.CO%3B2-S&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 11145836.1-7&rft.date=2001-01&rft_id=info:doi/10.1006/cyto.2000.0799&rft_id=info:pmid/11145836&rft.aulast=Pan&rft.aufirst=G&rft.au=Risser, P&rft.au=Mao, W&rft.au=Baldwin, DT&rft.au=Zhong, AW&rft.au=Filvaroff, E&rft.au=Yansura, D&rft.au=Lewis, L&rft.au=Eigenbrot, C&rft.au=Henzel, WJ&rft.au=Vandlen, R&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 11278614.20597-20602&rft.date=2001-06&rft_id=info:doi/10.1074/jbc.M010095200&rft_id=info:pmid/11278614&rft.aulast=Lin&rft.aufirst=H&rft.au=Ho, AS&rft.au=Haley-Vicente, D&rft.au=Zhang, J&rft.au=Bernal-Fussell, J&rft.au=Pace, AM&rft.au=Hansen, D&rft.au=Schweighofer, K&rft.au=Mize, NK&rft.au=Ford, JE&rft_id=https://doi.org/10.1074%2Fjbc.M010095200&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 85986577.1440-1446&rft.date=2001-08&rft_id=https://api.semanticscholar.org/CorpusID:85986577#id-name=S2CID&rft_id=info:pmid/11466363&rft_id=info:doi/10.4049/jimmunol.167.3.1440&rft.aulast=Debets&rft.aufirst=R&rft.au=Timans, JC&rft.au=Homey, B&rft.au=Zurawski, S&rft.au=Sana, TR&rft.au=Lo, S&rft.au=Wagner, J&rft.au=Edwards, G&rft.au=Clifford, T&rft.au=Menon, S&rft.au=Bazan, JF&rft.au=Kastelein, RA&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 11574262.536-537&rft.date=2001-10&rft_id=info:doi/10.1016/S1471-4906(01)02040-3&rft_id=info:pmid/11574262&rft.aulast=Sims&rft.aufirst=JE&rft.au=Nicklin, MJ&rft.au=Bazan, JF&rft.au=Barton, JL&rft.au=Busfield, SJ&rft.au=Ford, JE&rft.au=Kastelein, RA&rft.au=Kumar, S&rft.au=Lin, H&rft.au=Mulero, JJ&rft.au=Pan, J&rft.au=Pan, Y&rft.au=Smith, DE&rft.au=Young, PR&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 11991722.718-725&rft.date=2002-05&rft_id=info:doi/10.1006/geno.2002.6751&rft_id=info:pmid/11991722&rft.aulast=Nicklin&rft.aufirst=MJ&rft.au=Barton, JL&rft.au=Nguyen, M&rft.au=FitzGerald, MG&rft.au=Duff, GW&rft.au=Kornman, K&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
  • 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 11991723.726-733&rft.date=2002-05&rft_id=info:doi/10.1006/geno.2002.6752&rft_id=info:pmid/11991723&rft.aulast=Taylor&rft.aufirst=SL&rft.au=Renshaw, BR&rft.au=Garka, KE&rft.au=Smith, DE&rft.au=Sims, JE&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
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  • 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 12381835.13723-13728&rft.date=2002-10&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129755#id-name=PMC&rft_id=info:pmid/12381835&rft_id=info:doi/10.1073/pnas.212519099&rft_id=info:bibcode/2002PNAS...9913723B&rft.aulast=Bufler&rft.aufirst=P&rft.au=Azam, T&rft.au=Gamboni-Robertson, F&rft.au=Reznikov, LL&rft.au=Kumar, S&rft.au=Dinarello, CA&rft.au=Kim, SH&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129755&rfr_id=info:sid/en.wikipedia.org:Interleukin 37" class="Z3988">
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  • Overview of all the structural information available in the PDB for UniProt: Q9NZH6 (Interleukin-37) at the PDBe-KB.