Interleukin 30

Interleukin 30 (IL-30) forms one chain of the heterodimeric cytokine called interleukin 27 (IL-27), thus it is also called IL27-p28. IL-27 is composed of α chain p28 and β chain Epstain-Barr induce gene-3 (EBI3). The p28 subunit, or IL-30, has an important role as a part of IL-27, but it can be secreted as a separate monomer and has its own functions in the absence of EBI3.[5][6] The discovery of IL-30 as individual cytokine is relatively new and thus its role in the modulation of the immune response is not fully understood.

IL27
Identifiers
AliasesIL27, IL-27, IL-27A, IL27A, IL27p28, IL30, p28, Interleukin 30, IL-30, interleukin 27
External IDsOMIM: 608273 MGI: 2384409 HomoloGene: 17087 GeneCards: IL27
Orthologs
SpeciesHumanMouse
Entrez

246778

246779

Ensembl

ENSG00000197272

ENSMUSG00000044701

UniProt

Q8NEV9

Q8K3I6

RefSeq (mRNA)

NM_145659

NM_145636

RefSeq (protein)

NP_663634

NP_663611

Location (UCSC)Chr 16: 28.5 – 28.51 MbChr 7: 126.19 – 126.19 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

IL-30 monomer is believed to have some functions similar to IL-27, even though there are more information and research on the IL-27 than IL-30. Both IL-27 and IL-30 alone can regulate inflammation by inhibiting Th17 cells production using STAT1 pathway. Although IL-30 has similar effect as IL-27 on the production of IL-17, it has a lower efficiency than IL-27.[7] If secreted as a monomer, IL-30 was observed to act as a suppressor of the IL-27 signalling pathway. Similar to subunit p40 of IL-12 which competitively bind to IL-12 receptor (IL-12R) complex, IL-30 most likely binds to IL-27 receptor (IL-27R) receptor and thus prevents the binding of IL-27.[8] Since part of IL-27R is subunit gp130, which is also part of IL-6R, IL-30 can also act as an antagonist for IL-6 and thus suppress the production of Th17 and Th1 cells.[9] Receptor subunit gp130 plays an important role in receptors for multiple cytokines, there is a possibility that IL-30 can affect also other cytokine signalling.

IL-30 can also form an alternative heterodimer with the EBI3 homolog cytokine-like factor 1 (CLF) called p28/CLF. This complex is produced by dendritic cells. p28/CLF binds to IL-6Rα and gp130 subunits of IL-6 receptor. It stimulates NK cells and thus increases production of IFN-γ. It can also induce production of IgG1c, IgG2c and IgM.[10][11]

Artificially, IL-30 can form a heterodimer with p40 β chain of IL-12 creating novel recombinant protein p28/p40 that is biologically active, which suggest the α and β chains of cytokines from IL-12 family may form different heterodimers in nature. This recombinant protein has suppressive effect on Th17 cells that comes from inhibiting the activation of STAT1 and STAT3 pathways, which are normally induced through gp130 receptor by IL-6 and IL-27. p28/p40 also inhibits the expansion of Th1 cells. Both of those functions could potentially be beneficial in treatment of some autoimmune diseases.[12]

It has been indicated that IL-30 plays a role in the regulation of prostate and breast cancer. It is linked with tumor progression as well as metastasization.[13][14]

Structure

IL-30 is a protein from the IL-6 cytokine family with molecular weight of 28 kilodaltons (thus the name IL27-p28). It is a member of the long-chain, 4-helix bundle family of cytokines, making it structurally similar to IL-6.[5]

The human gene for IL-30 is located on chromosome 16p11.[5] This gene for this molecule is now officially called IL-27 under HGNC guidelines.[15]

Cancer

IL-30 was found to be expressed in prostate [16] and breast cancer[17] by both cancer cells and tumor- or LN-infiltrating leukocytes, mostly myeloid cells, particularly in high-grade and stage of the diseases.[17]

Prostate cancer

Recent studies provided evidence that IL-30 is implicated in prostate cancer progression. IL-30, absent in normal prostatic epithelia, was found to be expressed by cancerous epithelia.  IL-30 expression by prostate cancer epithelia[13]  and leukocytes infiltrating tumor[18] and draining lymph nodes correlates with high-grade and advanced-stage prostate cancer.[19][13]

IL-30 promotes prostate cancer stem-like cells viability, self-renewal ability, tumorigenic and metastatic potential, it regulates, essentially via STAT1 and STAT3 signaling, a range of proinflammatory and chemokine/chemokine-receptor genes that promote tumor growth.[13]

IL-30 is emerging as a new and intriguing factor that may condition prostate cancer onset and progression. It is produced by tumor-infiltrating leukocytes, mostly myeloid derived cells.[18]

Discrimination of molecular pathways driving tumor growth and progression is important to identify novel prognostic markers and targets for new posibble treatments.[13]  Revealing that IL-30 displays cancer-promoting effects, strongly nominate this cytokine as a novel molecule shaping the tumor and lymph node microenvironment.

IL30 plays an important role in regulating prostate cancer stem-like cell behavior and metastatic potential. Hence targeting IL-30 signaling may be a potential therapeutic strategy against prostate cancer progression and recurrence.[13]

Targeting IL-30 in both cancer and host environment consistently inhibits tumor growth, ameliorates immune reactivity and reduces the risks of disease recurrence.[19] Studies suggested therapeutic monoclonal antibodies against IL-30 as a  for cancer treatment.[20]

Breast cancer

IL-30 was identified as a cytokine able to condition, in an autocrine or paracrine manner, gene expression profile, at times the viability, motility, and invasiveness of breast cancer cells and to generate an inflammatory and prometastatic milieu supporting tumor growth and progression.[21]

High levels of IL-30 in myeloid derived cells of tumor-draining lymph nodes from breast cancer patients have also proven to be an independent predictor of poor prognosis,[14]  thus suggesting the involvement of IL-30, produced by the host’s immune cells, in conditioning tumor behavior and patient outcome.[19]

Directly and/or by subverting multiple oncogenes and tumor suppressor genes, IL-30 favors cancer cell proliferation, migration, and dissemination. That may boost cancer cell expression of cytokines and chemokines, which promote myeloid cell recruitment and tumor progression.[17]

High level of IL-30 in breast cancer draining lymph nodes is an independent predictor of poor clinical outcome. [14] Identification of IL-30 in breast and draining lymph nodes may provide a new prognostic tool and target for a tailored breast cancer therapy in the emerging era of personalized medicine.[17]

Therapeutic use

IL-30, or a heterodimer p28/p40, could potentially be used as an immunosuppressant for autoimmune and severe systematic inflammatory diseases.[8][12] IL-30 could also be a potential target for cancer treatment.[13]

References
  1. GRCh38: Ensembl release 89: ENSG00000197272 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000044701 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, et al. (June 2002). "IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells". Immunity. 16 (6): 779–90. doi:10.1016/S1074-7613(02)00324-2. PMID 12121660.
  6. Catalan-Dibene J, McIntyre LL, Zlotnik A (October 2018). "Interleukin 30 to Interleukin 40". Journal of Interferon & Cytokine Research. 38 (10): 423–439. doi:10.1089/jir.2018.0089. PMC 6206549. PMID 30328794.
  7. Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, et al. (September 2006). "Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system". Nature Immunology. 7 (9): 937–45. doi:10.1038/ni1376. PMID 16906166. S2CID 20631239.
  8. Shimozato O, Sato A, Kawamura K, Chiyo M, Ma G, Li Q, Tagawa M (September 2009). "The secreted form of p28 subunit of interleukin (IL)-27 inhibits biological functions of IL-27 and suppresses anti-allogeneic immune responses". Immunology. 128 (1 Suppl): e816-25. doi:10.1111/j.1365-2567.2009.03088.x. PMC 2753920. PMID 19740343.
  9. Stumhofer JS, Tait ED, Quinn WJ, Hosken N, Spudy B, Goenka R, et al. (December 2010). "A role for IL-27p28 as an antagonist of gp130-mediated signaling". Nature Immunology. 11 (12): 1119–26. doi:10.1038/ni.1957. PMC 3059498. PMID 21057510.
  10. Crabé S, Guay-Giroux A, Tormo AJ, Duluc D, Lissilaa R, Guilhot F, et al. (December 2009). "The IL-27 p28 subunit binds cytokine-like factor 1 to form a cytokine regulating NK and T cell activities requiring IL-6R for signaling". Journal of Immunology. 183 (12): 7692–702. doi:10.4049/jimmunol.0901464. PMID 19933857. S2CID 1575993.
  11. Tormo AJ, Meliani Y, Beaupré LA, Sharma M, Fritz JH, Elson G, et al. (August 2013). "The composite cytokine p28/cytokine-like factor 1 sustains B cell proliferation and promotes plasma cell differentiation". Journal of Immunology. 191 (4): 1657–65. doi:10.4049/jimmunol.1201595. PMID 23836062. S2CID 3157282.
  12. Wang RX, Yu CR, Mahdi RM, Egwuagu CE (October 2012). "Novel IL27p28/IL12p40 cytokine suppressed experimental autoimmune uveitis by inhibiting autoreactive Th1/Th17 cells and promoting expansion of regulatory T cells". The Journal of Biological Chemistry. 287 (43): 36012–21. doi:10.1074/jbc.M112.390625. PMC 3476269. PMID 22936807.
  13. Sorrentino C, Ciummo SL, Cipollone G, Caputo S, Bellone M, Di Carlo E (May 2018). "Interleukin-30/IL27p28 Shapes Prostate Cancer Stem-like Cell Behavior and Is Critical for Tumor Onset and Metastasization". Cancer Research. 78 (10): 2654–2668. doi:10.1158/0008-5472.CAN-17-3117. PMID 29487200.
  14. Airoldi I, Cocco C, Sorrentino C, Angelucci D, Di Meo S, Manzoli L, et al. (November 2016). "Interleukin-30 Promotes Breast Cancer Growth and Progression". Cancer Research. 76 (21): 6218–6229. doi:10.1158/0008-5472.CAN-16-0189. PMID 27550449.
  15. http://www.gene.ucl.ac.uk/nomenclature/data/get_data.php?hgnc_id=19157%5B%5D
  16. Sorrentino C, Ciummo SL, Cipollone G, Caputo S, Bellone M, Di Carlo E (May 2018). "Interleukin-30/IL27p28 Shapes Prostate Cancer Stem-like Cell Behavior and Is Critical for Tumor Onset and Metastasization". Cancer Research. 78 (10): 2654–2668. doi:10.1158/0008-5472.can-17-3117. PMID 29487200.
  17. Airoldi I, Cocco C, Sorrentino C, Angelucci D, Di Meo S, Manzoli L, et al. (November 2016). "Interleukin-30 Promotes Breast Cancer Growth and Progression". Cancer Research. 76 (21): 6218–6229. doi:10.1158/0008-5472.can-16-0189. PMID 27550449.
  18. Di Meo S, Airoldi I, Sorrentino C, Zorzoli A, Esposito S, Di Carlo E (February 2014). "Interleukin-30 expression in prostate cancer and its draining lymph nodes correlates with advanced grade and stage". Clinical Cancer Research. 20 (3): 585–94. doi:10.1158/1078-0432.ccr-13-2240. PMID 24277453.
  19. Sorrentino C, Yin Z, Ciummo S, Lanuti P, Lu LF, Marchisio M, et al. (July 2019). "Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival". Journal for Immunotherapy of Cancer. 7 (1): 201. doi:10.1186/s40425-019-0668-z. PMC 6670138. PMID 31366386.
  20. Catalan-Dibene J, McIntyre LL, Zlotnik A (October 2018). "Interleukin 30 to Interleukin 40". Journal of Interferon & Cytokine Research. 38 (10): 423–439. doi:10.1089/jir.2018.0089. PMC 6206549. PMID 30328794.
  21. Airoldi I, Cocco C, Sorrentino C, Angelucci D, Di Meo S, Manzoli L, et al. (November 2016). "Interleukin-30 Promotes Breast Cancer Growth and Progression". Cancer Research. 76 (21): 6218–6229. doi:10.1158/0008-5472.can-16-0189. PMID 27550449.
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