Interleukin 37 Explained

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.^[1]

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.^[2] 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.^[3] Full maturation requires cleavage by Caspase-1.^[4]

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.^{[5] [6]}

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

Further reading

• Nold-Petry CA, Lo CY, Rudloff I, Elgass KD, Li S, Gantier MP, Lotz-Havla AS, Gersting SW, Cho SX, Lao JC, Ellisdon AM, Rotter B, Azam T, Mangan NE, Rossello FJ, Whisstock JC, Bufler P, Garlanda C, Mantovani A, Dinarello CA, Nold MF . 6 . 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 . April 2015 . 25729923 . 10.1038/ni.3103 . 24578661 .
• Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA . IL-37 is a fundamental inhibitor of innate immunity . Nature Immunology . 11 . 11 . 1014–1022 . November 2010 . 20935647 . 3537119 . 10.1038/ni.1944 .
• Nicklin MJ, Weith A, Duff GW . 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 . January 1994 . 8188271 . 10.1006/geno.1994.1076 .
• Nothwang HG, Strahm B, Denich D, Kübler M, Schwabe J, Gingrich JC, Jauch A, Cox A, Nicklin MJ, Kurnit DM, Hildebrandt F . 6 . 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 . May 1997 . 9169134 . 10.1006/geno.1997.4654 .
• Kumar S, McDonnell PC, Lehr R, Tierney L, Tzimas MN, Griswold DE, Capper EA, Tal-Singer R, Wells GI, Doyle ML, Young PR . 6 . Identification and initial characterization of four novel members of the interleukin-1 family . The Journal of Biological Chemistry . 275 . 14 . 10308–10314 . April 2000 . 10744718 . 10.1074/jbc.275.14.10308 . free .
• Busfield SJ, Comrack CA, Yu G, Chickering TW, Smutko JS, Zhou H, Leiby KR, Holmgren LM, Gearing DP, Pan Y . 6 . Identification and gene organization of three novel members of the IL-1 family on human chromosome 2 . Genomics . 66 . 2 . 213–216 . June 2000 . 10860666 . 10.1006/geno.2000.6184 .
• Barton JL, Herbst R, Bosisio D, Higgins L, Nicklin MJ . 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 . November 2000 . 11093146 . 10.1002/1521-4141(200011)30:11<3299::AID-IMMU3299>3.0.CO;2-S . free .
• Pan G, Risser P, Mao W, Baldwin DT, Zhong AW, Filvaroff E, Yansura D, Lewis L, Eigenbrot C, Henzel WJ, Vandlen R . 6 . IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp . Cytokine . 13 . 1 . 1–7 . January 2001 . 11145836 . 10.1006/cyto.2000.0799 .
• Lin H, Ho AS, Haley-Vicente D, Zhang J, Bernal-Fussell J, Pace AM, Hansen D, Schweighofer K, Mize NK, Ford JE . 6 . Cloning and characterization of IL-1HY2, a novel interleukin-1 family member . The Journal of Biological Chemistry . 276 . 23 . 20597–20602 . June 2001 . 11278614 . 10.1074/jbc.M010095200 . free .
• Debets R, Timans JC, Homey B, Zurawski S, Sana TR, Lo S, Wagner J, Edwards G, Clifford T, Menon S, Bazan JF, Kastelein RA . 6 . 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 . August 2001 . 11466363 . 10.4049/jimmunol.167.3.1440 . 85986577 .
• Sims JE, Nicklin MJ, Bazan JF, Barton JL, Busfield SJ, Ford JE, Kastelein RA, Kumar S, Lin H, Mulero JJ, Pan J, Pan Y, Smith DE, Young PR . 6 . A new nomenclature for IL-1-family genes . Trends in Immunology . 22 . 10 . 536–537 . October 2001 . 11574262 . 10.1016/S1471-4906(01)02040-3 .
• Nicklin MJ, Barton JL, Nguyen M, FitzGerald MG, Duff GW, Kornman K . A sequence-based map of the nine genes of the human interleukin-1 cluster . Genomics . 79 . 5 . 718–725 . May 2002 . 11991722 . 10.1006/geno.2002.6751 .
• Taylor SL, Renshaw BR, Garka KE, Smith DE, Sims JE . Genomic organization of the interleukin-1 locus . Genomics . 79 . 5 . 726–733 . May 2002 . 11991723 . 10.1006/geno.2002.6752 .
• Kumar S, Hanning CR, Brigham-Burke MR, Rieman DJ, Lehr R, Khandekar S, Kirkpatrick RB, Scott GF, Lee JC, Lynch FJ, Gao W, Gambotto A, Lotze MT . 6 . 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 . April 2002 . 12096920 . 10.1006/cyto.2002.0873 .
• Bufler P, Azam T, Gamboni-Robertson F, Reznikov LL, Kumar S, Dinarello CA, Kim SH . 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 . October 2002 . 12381835 . 129755 . 10.1073/pnas.212519099 . free . 2002PNAS...9913723B .
• Grimsby S, Jaensson H, Dubrovska A, Lomnytska M, Hellman U, Souchelnytskyi S . 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 . November 2004 . 15527767 . 10.1016/j.febslet.2004.09.069 . 82568 . free .

Notes and References

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