Interleukin 37

Last updated
IL37
Identifiers
Aliases IL37 , FIL1, FIL1(ZETA), FIL1Z, IL-1F7, IL-1H, IL-1H4, IL-1RP1, IL-37, IL1F7, IL1H4, IL1RP1, interleukin 37, IL-23
External IDs OMIM: 605510 HomoloGene: 105713 GeneCards: IL37
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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

n/a

Location (UCSC) Chr 2: 112.91 – 112.92 Mb n/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]

Contents

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

Related Research Articles

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<span class="mw-page-title-main">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.

<span class="mw-page-title-main">Interleukin 18</span> Protein-coding gene in the species Homo sapiens

Interleukin-18 (IL-18), also known as interferon-gamma inducing factor is a protein which in humans is encoded by the IL18 gene. The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and non-hematopoietic cells, have the potential to produce IL-18. It was first described in 1989 as a factor that induced interferon-γ (IFN-γ) production in mouse spleen cells. Originally, IL-18 production was recognized in Kupffer cells, liver-resident macrophages. However, IL-18 is constitutively expressed in non-hematopoietic cells, such as intestinal epithelial cells, keratinocytes, and endothelial cells. IL-18 can modulate both innate and adaptive immunity and its dysregulation can cause autoimmune or inflammatory diseases.

<span class="mw-page-title-main">Interleukin-1 receptor antagonist protein</span> Protein and coding gene in humans

The interleukin-1 receptor antagonist protein (IL-1RN) is a protein that in humans is encoded by the IL1RN gene.

<span class="mw-page-title-main">STAT6</span> Protein and coding gene in humans

Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor complex to the nucleus and activate gene expression. Similarly as other STAT family proteins, STAT6 is also activated by growth factors and cytokines. STAT6 is mainly activated by cytokines interleukin-4 and interleukin-13.

<span class="mw-page-title-main">Interleukin 1 receptor, type I</span>

Interleukin 1 receptor, type I (IL1R1) also known as CD121a, is an interleukin receptor. IL1R1 also denotes its human gene.

<span class="mw-page-title-main">Interleukin 36 receptor antagonist</span> Protein-coding gene in the species Homo sapiens

Interleukin 36 receptor antagonist (IL-36RA) is a member of the interleukin-36 family of cytokines. It was previously named Interleukin-1 family member 5 (IL1F5).

<span class="mw-page-title-main">IL18BP</span> Protein-coding gene in the species Homo sapiens

Interleukin-18-binding protein is a protein that in humans is encoded by the IL18BP gene.

<span class="mw-page-title-main">Interleukin 11 receptor alpha subunit</span> Protein-coding gene in the species Homo sapiens

Interleukin 11 receptor, alpha subunit is a subunit of the interleukin 11 receptor. IL11RA is its human gene.

<span class="mw-page-title-main">IL36G</span> Protein-coding gene in the species Homo sapiens

Interleukin-36 gamma previously known as interleukin-1 family member 9 (IL1F9) is a protein that in humans is encoded by the IL36G gene.

<span class="mw-page-title-main">IL36A</span> Protein-coding gene in the species Homo sapiens

Interleukin-36 alpha also known as interleukin-1 family member 6 (IL1F6) is a protein that in humans is encoded by the IL36A gene.

<span class="mw-page-title-main">IL1F10</span> Human protein and coding gene

Interleukin-1 family member 10 is a protein that in humans is encoded by the IL1F10 gene.

<span class="mw-page-title-main">IL36B</span> Protein-coding gene in the species Homo sapiens

Interleukin-36 beta also known as interleukin-1 family member 8 (IL1F8) is a protein that in humans is encoded by the IL36B gene.

<span class="mw-page-title-main">SIGIRR</span> Protein-coding gene in the species Homo sapiens

Single Ig IL-1-related receptor (SIGIRR), also called Toll/Interleukin-1 receptor 8 (TIR8) or Interleukin-1 receptor 8 (IL-1R8), is transmembrane protein encoded by gene SIGIRR, which modulate inflammation, immune response, and tumorigenesis of colonic epithelial cells.

<span class="mw-page-title-main">IL1RL2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">IL18R1</span> Protein-coding gene in the species Homo sapiens

The interleukin-18 receptor 1 (IL-18R1) is an interleukin receptor of the immunoglobulin superfamily. IL18R1 is its human gene. IL18R1 is also known as CDw218a.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

<span class="mw-page-title-main">IL1RL1</span> Protein-coding gene in the species Homo sapiens

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000125571 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 3 4 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. 1 2 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. 1 2 3 4 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. 1 2 3 4 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. 1 2 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