Interleukin 20 Explained

Interleukin 20 (IL20) is a protein that is in humans encoded by the IL20 gene which is located in close proximity to the IL-10 gene on the 1q32 chromosome.[1] [2] IL-20 is a part of an IL-20 subfamily which is a part of a larger IL-10 family.

IL-20 subfamily also includes other cytokines, including IL-19, IL-20, IL-22, IL-24, and IL-26. Members of the cytokine IL-20 subfamily form an important link between the immune system and epithelial tissues due to the fact that receptors for these cytokines are highly expressed on epithelial cells and are almost exclusively produced by cells of the immune system.[3]

IL-20 requires an IL-β-subunit receptor (IL-20RB) for signaling, which can form a functional heterodimeric receptor with either the α-subunit of the IL-20 receptor (IL-20RA) or the α1-subunit of the IL-22 receptor (IL-22RA1). Both of these receptor variants allow efficient IL-20 signaling. Receptors for IL-20 are expressed in the skin, lungs, ovary, testes, and placenta. IL-20 is mainly produced by myeloid cells such as monocytes, granulocytes, and dendritic cells but can also be produced by keratinocytes and fibroblasts. The expression of IL-20 is stimulated by IL-1β, IL-17, IL-22, TNF, and LPS. The main cellular targets of IL-20 are keratinocytes, endothelial cells, and adipocytes.[4] IL-20 has been shown to transduce its signal through signal transducer and activator of transcription 3 (STAT3) in keratinocytes.[5]

Function

IL-20 has a broad range of functions and is involved in a variety of immune and non-immune processes in the body. For example, IL-20 is involved in the process of wound healing, proliferation of epithelial cells, prevention of apoptosis of epithelial cells, regulation of differentiation of keratinocytes during inflammation, the expansion of multipotential hematopoietic progenitor cells, and more.[6]

A specific receptor for this cytokine is highly upregulated in psoriatic skin.[7] Dysfunctional regulation of IL-20 could lead to uncontrollable wound healing in psoriasis, which could be a contributing factor to the pathogenesis of this disease.

Because IL-20 is involved in the promotion of proliferation of epithelial cells it is also linked to the development of cancer. Receptors for IL-20 are very often expressed on tumorous cells of epithelial origin.[8] High expression of IL-20 is also associated with bladder cancer. On the other hand, IL-20 is known to prevent tissue damage as a result of chronic inflammation which may reduce the chance of developing cancer. So the role of IL-20 in cancer development is ambiguous and needs to be further explored.[9]

IL-20 is an angiogenesis factor and is highly expressed in artery plaques found in patients with atherosclerosis.[10]

In rheumatoid arthritis

IL-20 is involved in many stages of rheumatoid arthritis (RA) progression.[11] IL-20 stimulates the secretion of chemokines MCP-1 and IL-8 in synovial fibroblasts, which attract neutrophils and T-cells.[12] [13] IL-20 is also an upstream regulator of TNF-α, IL-1, and IL-6, which are involved in the pathogenesis of RA. IL-20 is highly expressed in the synovial fluid of RA patients. Serum levels of IL-20 are not different from those of healthy controls, suggesting that IL-20 is involved in the pathogenesis of RA only at local sites of inflammation. Receptors for IL-20 are highly expressed in the synovial membranes of RA patients. Due to the clear association of IL-20 with RA, anti-IL-20 antibody is now in a clinical trial for RA.[14]

Antibody

Anti-IL-20 monoclonal antibodies have been researched as clinical candidates for the treatment or prevention of psoriasis, rheumatoid arthritis, atherosclerosis, osteoporosis, and stroke.[15] The anti-IL-20 antibody has been shown to reduce the severity of RA in rats, mitigate bone destruction, and more. The anti-IL-20 antibody neutralizes not only IL-20 signaling but also decreases TNF-α, IL-1, and IL-6 signaling in vivo. A human recombinant monoclonal antibody against IL-20 developed by Novo Nordisk Inc. now entered the IIb phase of a clinical trial.

Notes and References

  1. Rutz S, Wang X, Ouyang W . The IL-20 subfamily of cytokines--from host defence to tissue homeostasis . Nature Reviews. Immunology . 14 . 12 . 783–795 . December 2014 . 25421700 . 10.1038/nri3766 . 29114703 .
  2. Kontogiorgis CA, Hadjipavlou-Litina DJ . Non steroidal anti-inflammatory and anti-allergy agents . Current Medicinal Chemistry . 9 . 1 . 89–98 . January 2002 . 11860351 . 10.2174/187152306778017683 .
  3. Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG . Regulation and functions of the IL-10 family of cytokines in inflammation and disease . Annual Review of Immunology . 29 . 1 . 71–109 . 2011-04-23 . 21166540 . 10.1146/annurev-immunol-031210-101312 .
  4. Sa SM, Valdez PA, Wu J, Jung K, Zhong F, Hall L, Kasman I, Winer J, Modrusan Z, Danilenko DM, Ouyang W . 6 . The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis . Journal of Immunology . 178 . 4 . 2229–2240 . February 2007 . 17277128 . 10.4049/jimmunol.178.4.2229 . 1870754 . free .
  5. Web site: Entrez Gene: Interleukin 20.
  6. Kragstrup TW, Greisen SR, Nielsen MA, Rhodes C, Stengaard-Pedersen K, Hetland ML, Hørslev-Petersen K, Junker P, Østergaard M, Hvid M, Vorup-Jensen T, Robinson WH, Sokolove J, Deleuran B . 6 . The interleukin-20 receptor axis in early rheumatoid arthritis: novel links between disease-associated autoantibodies and radiographic progression . Arthritis Research & Therapy . 18 . 1 . 61 . March 2016 . 26968800 . 4788924 . 10.1186/s13075-016-0964-7 . 2024-02-08 . free .
  7. Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, Itami S, Nickoloff BJ, DiGiovanni J . 6 . Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model . Nature Medicine . 11 . 1 . 43–49 . January 2005 . 15592573 . 10.1038/nm1162 . 20474354 .
  8. Lee SJ, Lee EJ, Kim SK, Jeong P, Cho YH, Yun SJ, Kim S, Kim GY, Choi YH, Cha EJ, Kim WJ, Moon SK . 6 . Identification of pro-inflammatory cytokines associated with muscle invasive bladder cancer; the roles of IL-5, IL-20, and IL-28A . PLOS ONE . 7 . 9 . e40267 . 2012-09-04 . 22962576 . 3433484 . 10.1371/journal.pone.0040267 . 2012PLoSO...740267L . Frangogiannis N . free .
  9. Meira LB, Bugni JM, Green SL, Lee CW, Pang B, Borenshtein D, Rickman BH, Rogers AB, Moroski-Erkul CA, McFaline JL, Schauer DB, Dedon PC, Fox JG, Samson LD . 6 . DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice . The Journal of Clinical Investigation . 118 . 7 . 2516–2525 . July 2008 . 18521188 . 2423313 . 10.1172/JCI35073 .
  10. Chen WY, Cheng BC, Jiang MJ, Hsieh MY, Chang MS . IL-20 is expressed in atherosclerosis plaques and promotes atherosclerosis in apolipoprotein E-deficient mice . Arteriosclerosis, Thrombosis, and Vascular Biology . 26 . 9 . 2090–2095 . September 2006 . 16778121 . 10.1161/01.ATV.0000232502.88144.6f . 8237021 . free .
  11. Hsu YH, Chang MS . IL-20 in rheumatoid arthritis . Drug Discovery Today . 22 . 6 . 960–964 . June 2017 . 26297177 . 10.1016/j.drudis.2015.08.002 .
  12. Hsu YH, Li HH, Hsieh MY, Liu MF, Huang KY, Chin LS, Chen PC, Cheng HH, Chang MS . 6 . Function of interleukin-20 as a proinflammatory molecule in rheumatoid and experimental arthritis . Arthritis and Rheumatism . 54 . 9 . 2722–2733 . September 2006 . 16947773 . 10.1002/art.22039 . free .
  13. Kragstrup TW, Otkjaer K, Holm C, Jørgensen A, Hokland M, Iversen L, Deleuran B . The expression of IL-20 and IL-24 and their shared receptors are increased in rheumatoid arthritis and spondyloarthropathy . Cytokine . 41 . 1 . 16–23 . January 2008 . 18061474 . 10.1016/j.cyto.2007.10.004 .
  14. Hsu YH, Chang MS . The therapeutic potential of anti-interleukin-20 monoclonal antibody . Cell Transplantation . 23 . 4–5 . 631–639 . May 2014 . 24816455 . 10.3727/096368914X678319 . 10729459 .
  15. Hsu YH, Chen WY, Chan CH, Wu CH, Sun ZJ, Chang MS . Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss . The Journal of Experimental Medicine . 208 . 9 . 1849–1861 . August 2011 . 21844205 . 3171097 . 10.1084/jem.20102234 .

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