Interleukin 37

"IL-37" redirects here. For the road, see Illinois Route 37.
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

27178

n/a

Ensembl

ENSG00000125571

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UniProt

Q9NZH6

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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

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Location (UCSC)Chr 2: 112.91 – 112.92 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

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

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000125571 – Ensembl, 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.
  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.
  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

  • Overview of all the structural information available in the PDB for UniProt: Q9NZH6 (Interleukin-37) at the PDBe-KB.