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]
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.[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
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
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
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
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
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
- Interleukin-1 family
- Interleukin 18
- Interleukin 18 receptor
- Interleukin 18 binding protein
- Inflammation
- Carcinogenesis
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000125571 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
