The mechanism of IL-37 functions is still to be elucidated. Known functions of IL-37 includeanti-inflammatory effects, tumor suppression, and antimicrobial responses. IL-37 actsintracellulary andextracellulary, classifying the cytokine as dual-function.[3]
IL-37, similar to other members of theinterleukin-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 byCaspase-1.[7]
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 followingnecrosis orapoptosis.[6] IL-37 has two similaramino acid residues withIL-18, and thus extracellular IL-37 can interact withIL-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 withIL-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]
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 andovarian cancer are associated with elevated expression of IL-37.Colon cancer,lung cancer,Multiple Myeloma, andHepatoma Carcinoma were correlated with decreased expression of IL-37 expression in affected areas.[5]
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.PMID25729923.S2CID24578661.
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.PMID8188271.
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.PMID9169134.
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.PMID10860666.
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.PMID11145836.
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.PMID11466363.S2CID85986577.
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.PMID11574262.
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.PMID11991722.
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.PMID11991723.
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.PMID12096920.
