# IL27

## Overview
Interleukin 27 (IL-27) is a cytokine encoded by the IL27 gene, playing a pivotal role in the regulation of immune responses. As a member of the IL-12 cytokine family, IL-27 is a heterodimeric protein composed of two subunits: IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3). The IL-27p28 subunit is characterized by a four-helical bundle structure, while EBI3 functions as a soluble receptor-like component. IL-27 is involved in both pro-inflammatory and anti-inflammatory processes, influencing T cell differentiation, B cell activity, and natural killer (NK) cell function. It signals through the gp130/WSX-1 receptor complex, activating various intracellular pathways such as JAK/STAT, which are crucial for immune cell proliferation and differentiation. The cytokine's dual role in immune modulation makes it a significant focus of research in autoimmune diseases and cancer immunotherapy (Hall2012The; AparicioSiegmund2015The; Yoshida2009Interleukin).

## Structure
Interleukin 27 (IL-27) is a heterodimeric cytokine composed of two subunits: IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3). The IL-27p28 subunit is a four-helical bundle cytokine, similar to other members of the IL-6 family, while EBI3 functions as a soluble receptor with two fibronectin-like domains (AparicioSiegmund2015The; Bosmann2013Modulation). The primary structure of IL-27 involves the amino acid sequences of these subunits, with p28 being a 243 amino acid protein and EBI3 a 229 amino acid protein (Bosmann2013Modulation). 

The secondary structure of IL-27 includes alpha helices, as indicated by the presence of long-chain four-helix bundle motifs in the p28 subunit (Hall2012The). The tertiary structure refers to the 3D folding of these subunits, which is crucial for their function. The quaternary structure involves the non-covalent heterodimeric assembly of p28 and EBI3, which is necessary for the cytokine's secretion and biological activity (Batten2007The; Iwasaki2015Interleukin27).

IL-27 may undergo post-translational modifications such as glycosylation, which can influence its stability and function (Bosmann2013Modulation). The subunits of IL-27 can also participate in other cytokine complexes, highlighting the plasticity and complexity of its role in the cytokine network (AparicioSiegmund2015The).

## Function
Interleukin 27 (IL-27) is a cytokine involved in complex immune regulation, acting as both a pro-inflammatory and anti-inflammatory agent. It is part of the IL-12 family and is composed of the subunits p28 and EBI3. IL-27 signals through the gp130/WSX-1 receptor complex, activating pathways such as JAK/STAT, ERK, p38 MAPK, and Akt, which are crucial for cellular proliferation and differentiation (AparicioSiegmund2015The).

In healthy human cells, IL-27 plays a significant role in T cell differentiation and function. It promotes Th1 differentiation by inducing IL-12Rβ2 expression, enabling naive CD4+ T cells to produce IFN-γ, essential for cellular immunity (Yoshida2009Interleukin). IL-27 also enhances the cytotoxic activity of CD8+ T cells and promotes IFN-γ production, contributing to anti-tumor immunity (Yoshida2009Interleukin).

IL-27 has anti-inflammatory properties, suppressing Th17 cell development by inhibiting the expression of RORγt and promoting IL-10 production, which helps prevent excessive inflammation (AparicioSiegmund2015The; Yoshida2009Interleukin). It also influences B cell differentiation and enhances NK cell activity, further contributing to immune regulation (Yoshida2009Interleukin).

## Clinical Significance
Mutations and alterations in the IL27 gene have been implicated in various diseases, particularly those involving immune dysregulation. In chronic obstructive pulmonary disease (COPD), a non-synonymous variant rs181206 in the IL27 gene is associated with the disease, resulting in a leucine to proline change in the interleukin-27 subunit alpha protein. This variant's effect in COPD is concordant with inflammatory bowel disease but discordant with diabetes, suggesting a biological link between autoimmune diseases and COPD (Hobbs2016Exome).

IL-27 is also involved in autoimmune rheumatologic diseases such as systemic lupus erythematosus (SLE) and Behçet's disease (BD). In SLE, genetic polymorphisms like rs153109 A/G in the IL27 gene are associated with disease susceptibility. In BD, IL-27 modulates the immune response by suppressing Th17 cells, which are crucial in the disease's pathogenesis (Shahi2020IL27).

In rheumatoid arthritis (RA), IL-27 regulates ectopic lymphoid-like structure development in inflamed synovial tissues. Low IL-27 expression correlates with increased incidence of these structures, exacerbating synovitis and inflammation (Jones2015Interleukin27). IL-27's role in limiting Th17 cell expansion is significant in managing autoimmune diseases like RA and inflammatory bowel disease (Hall2012The).

## Interactions
Interleukin 27 (IL-27) is a heterodimeric cytokine composed of the p28 and Epstein-Barr Virus-Induced 3 (Ebi3) subunits. It interacts with the IL-27 receptor complex, which includes the IL-27Rα and gp130 subunits, to initiate signaling pathways that involve the activation of Janus Kinases (JAKs) and the nuclear translocation of STAT1 and STAT3 transcription factors (NA2022Micrographs). The IL-27 complex exhibits a molecular architecture with 'sites 1-3', where site 1 involves the interaction between p28 and Ebi3, forming the heterodimeric cytokine IL-27. Site 2 involves interactions between p28 and IL-27Rα, as well as between Ebi3 and IL-27Rα. Site 3 involves the interaction of the D1 Ig domain of gp130 with both p28 and Ebi3 (NA2022Micrographs).

IL-27 also interacts with cytokine-like factor 1 (CLF) to form a complex that regulates NK and T cell activities. This complex requires IL-6R for signaling, indicating a shared pathway with other cytokines like IL-6 (Crabé2009The). The p28 subunit of IL-27 can independently form a secreted complex with CLF, suggesting flexibility in its interaction capabilities (Crabé2009The).


## References


[1. (Bosmann2013Modulation) Markus Bosmann and Peter A Ward. Modulation of inflammation by interleukin-27. Journal of Leukocyte Biology, 94(6):1159–1165, July 2013. URL: http://dx.doi.org/10.1189/jlb.0213107, doi:10.1189/jlb.0213107. This article has 73 citations and is from a peer-reviewed journal.](https://doi.org/10.1189/jlb.0213107)

[2. (Jones2015Interleukin27) Gareth W. Jones, Michele Bombardieri, Claire J. Greenhill, Louise McLeod, Alessandra Nerviani, Vidalba Rocher-Ros, Anna Cardus, Anwen S. Williams, Costantino Pitzalis, Brendan J. Jenkins, and Simon A. Jones. Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis. Journal of Experimental Medicine, 212(11):1793–1802, September 2015. URL: http://dx.doi.org/10.1084/jem.20132307, doi:10.1084/jem.20132307. This article has 86 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1084/jem.20132307)

[3. (Iwasaki2015Interleukin27) Yukiko Iwasaki, Keishi Fujio, Tomohisa Okamura, and Kazuhiko Yamamoto. Interleukin-27 in t cell immunity. International Journal of Molecular Sciences, 16(2):2851–2863, January 2015. URL: http://dx.doi.org/10.3390/ijms16022851, doi:10.3390/ijms16022851. This article has 80 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms16022851)

[4. (Hall2012The) Aisling O’Hara Hall, Jonathan S. Silver, and Christopher A. Hunter. The Immunobiology of IL-27, pages 1–44. Elsevier, 2012. URL: http://dx.doi.org/10.1016/b978-0-12-394299-9.00001-1, doi:10.1016/b978-0-12-394299-9.00001-1. This article has 99 citations.](https://doi.org/10.1016/b978-0-12-394299-9.00001-1)

[5. (Shahi2020IL27) Abbas Shahi, Shima Afzali, Saeedeh Salehi, Saeed Aslani, Mahdi Mahmoudi, Ahmadreza Jamshidi, and Aliakbar Amirzargar. Il-27 and autoimmune rheumatologic diseases: the good, the bad, and the ugly. International Immunopharmacology, 84:106538, July 2020. URL: http://dx.doi.org/10.1016/j.intimp.2020.106538, doi:10.1016/j.intimp.2020.106538. This article has 12 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.intimp.2020.106538)

[6. (Batten2007The) Marcel Batten and Nico Ghilardi. The biology and therapeutic potential of interleukin 27. Journal of Molecular Medicine, 85(7):661–672, February 2007. URL: http://dx.doi.org/10.1007/s00109-007-0164-7, doi:10.1007/s00109-007-0164-7. This article has 93 citations.](https://doi.org/10.1007/s00109-007-0164-7)

[7. (Yoshida2009Interleukin) Hiroki Yoshida, Mako Nakaya, and Yoshiyuki Miyazaki. Interleukin 27: a double-edged sword for offense and defense. Journal of Leukocyte Biology, 86(6):1295–1303, October 2009. URL: http://dx.doi.org/10.1189/jlb.0609445, doi:10.1189/jlb.0609445. This article has 102 citations and is from a peer-reviewed journal.](https://doi.org/10.1189/jlb.0609445)

[8. (Hobbs2016Exome) Brian D. Hobbs, Margaret M. Parker, Han Chen, Taotao Lao, Megan Hardin, Dandi Qiao, Iwona Hawrylkiewicz, Pawel Sliwinski, Jae-Joon Yim, Woo Jin Kim, Deog Kyeom Kim, Peter J. Castaldi, Craig P. Hersh, Jarrett Morrow, Bartolome R. Celli, Victor M. Pinto-Plata, Gerald J. Criner, Nathaniel Marchetti, Raphael Bueno, Alvar Agustí, Barry J. Make, James D. Crapo, Peter M. Calverley, Claudio F. Donner, David A. Lomas, Emiel F. M. Wouters, Jorgen Vestbo, Peter D. Paré, Robert D. Levy, Stephen I. Rennard, Xiaobo Zhou, Nan M. Laird, Xihong Lin, Terri H. Beaty, Edwin K. Silverman, and Michael H. Cho. Exome array analysis identifies a common variant in il27 associated with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine, 194(1):48–57, July 2016. URL: http://dx.doi.org/10.1164/rccm.201510-2053OC, doi:10.1164/rccm.201510-2053oc. This article has 68 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1164/rccm.201510-2053OC)

[9. (Crabé2009The) Sandrine Crabé, Angélique Guay-Giroux, Aurélie Jeanne Tormo, Dorothée Duluc, Rami Lissilaa, Florence Guilhot, Ulrick Mavoungou-Bigouagou, Fouad Lefouili, Isabelle Cognet, Walter Ferlin, Greg Elson, Pascale Jeannin, and Jean-François Gauchat. 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. The Journal of Immunology, 183(12):7692–7702, December 2009. URL: http://dx.doi.org/10.4049/jimmunol.0901464, doi:10.4049/jimmunol.0901464. This article has 114 citations.](https://doi.org/10.4049/jimmunol.0901464)

[10. (AparicioSiegmund2015The) Samadhi Aparicio-Siegmund and Christoph Garbers. The biology of interleukin-27 reveals unique pro- and anti-inflammatory functions in immunity. Cytokine & Growth Factor Reviews, 26(5):579–586, October 2015. URL: http://dx.doi.org/10.1016/j.cytogfr.2015.07.008, doi:10.1016/j.cytogfr.2015.07.008. This article has 66 citations.](https://doi.org/10.1016/j.cytogfr.2015.07.008)

[11. (NA2022Micrographs) Caveney NA, Glassman CR, Jude KM, Tsutsumi N, and Garcia KC. Micrographs of the il-27 quaternary receptor signaling complex. December 2022. URL: http://dx.doi.org/10.6019/empiar-11486, doi:10.6019/empiar-11486. This article has 0 citations.](https://doi.org/10.6019/empiar-11486)