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
editThe 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
editIL-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
editThe 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
editIL-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
editIL-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
editIL-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
editReferences
edit- ^ 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 29552110.4711-4719&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">
- ^ 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">
- ^ 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
edit- 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">
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- 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">
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- 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">
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