| Structural highlights
Function
IL27A_MOUSE Associates with EBI3 to form the IL-27 interleukin, a heterodimeric cytokine which functions in innate immunity. IL-27 has pro- and anti-inflammatory properties, that can regulate T-helper cell development, suppress T-cell proliferation, stimulate cytotoxic T-cell activity, induce isotype switching in B-cells, and that has diverse effects on innate immune cells. Among its target cells are CD4 T-helper cells which can differentiate in type 1 effector cells (TH1), type 2 effector cells (TH2) and IL17 producing helper T-cells (TH17). It drives rapid clonal expansion of naive but not memory CD4 T-cells. It also strongly synergizes with IL-12 to trigger interferon-gamma/IFN-gamma production of naive CD4 T-cells, binds to the cytokine receptor WSX-1/TCCR which appears to be required but not sufficient for IL-27-mediated signal transduction. IL-27 potentiate the early phase of TH1 response and suppress TH2 and TH17 differentiation. It induces the differentiation of TH1 cells via two distinct pathways, p38 MAPK/TBX21- and ICAM1/ITGAL/ERK-dependent pathways. It also induces STAT1, STAT3, STAT4 and STAT5 phosphorylation and activates TBX21/T-Bet via STAT1 with resulting IL12RB2 up-regulation, an event crucial to TH1 cell commitment. It suppresses the expression of GATA3, the inhibitor TH1 cells development. In CD8 T-cells, it activates STATs as well as GZMB. IL-27 reveals to be a potent inhibitor of TH17 cell development and of IL-17 production. Indeed IL27 alone is also able to inhibit the production of IL17 by CD4 and CD8 T-cells. While IL-27 suppressed the development of pro-inflammatory Th17 cells via STAT1, it inhibits the development of anti-inflammatory inducible regulatory T-cells, iTreg, independently of STAT1. IL-27 has also an effect on cytokine production, it suppresses pro-inflammatory cytokine production such as IL2, IL4, IL5 and IL6 and activates suppressors of cytokine signaling such as SOCS1 and SOCS3. Apart from suppression of cytokine production, IL-27 also antagonizes the effects of some cytokines such as IL6 through direct effects on T-cells. Another important role of IL-27 is its antitumor activity as well as its antiangiogenic activity with activation of production of antiangiogenic chemokines such as IP-10/CXCL10 and MIG/CXCL9.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
Publication Abstract from PubMed
Interleukin-27 (IL-27) uniquely assembles p28 and EBI3 subunits to a heterodimeric cytokine that signals via IL-27Ralpha and gp130. To provide the structural framework for receptor activation by IL-27 and its emerging therapeutic targeting, we report here crystal structures of mouse IL-27 in complex with IL-27Ralpha and of human IL-27 in complex with SRF388, a monoclonal antibody undergoing clinical trials with oncology indications. One face of the helical p28 subunit interacts with EBI3, while the opposite face nestles into the interdomain elbow of IL-27Ralpha to juxtapose IL-27Ralpha to EBI3. This orients IL-27Ralpha for paired signaling with gp130, which only uses its immunoglobulin domain to bind to IL-27. Such a signaling complex is distinct from those mediated by IL-12 and IL-23. The SRF388 binding epitope on IL-27 overlaps with the IL-27Ralpha interaction site explaining its potent antagonistic properties. Collectively, our findings will facilitate the mechanistic interrogation, engineering, and therapeutic targeting of IL-27.
Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27.,Skladanowska K, Bloch Y, Strand J, White KF, Hua J, Aldridge D, Welin M, Logan DT, Soete A, Merceron R, Murphy C, Provost M, Bazan JF, Hunter CA, Hill JA, Savvides SN Cell Rep. 2022 Oct 18;41(3):111490. doi: 10.1016/j.celrep.2022.111490. PMID:36261006[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Hibbert L, Pflanz S, De Waal Malefyt R, Kastelein RA. IL-27 and IFN-alpha signal via Stat1 and Stat3 and induce T-Bet and IL-12Rbeta2 in naive T cells. J Interferon Cytokine Res. 2003 Sep;23(9):513-22. PMID:14565860 doi:http://dx.doi.org/10.1089/10799900360708632
- ↑ Lucas S, Ghilardi N, Li J, de Sauvage FJ. IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15047-52. doi:, 10.1073/pnas.2536517100. Epub 2003 Dec 1. PMID:14657353 doi:http://dx.doi.org/10.1073/pnas.2536517100
- ↑ Hisada M, Kamiya S, Fujita K, Belladonna ML, Aoki T, Koyanagi Y, Mizuguchi J, Yoshimoto T. Potent antitumor activity of interleukin-27. Cancer Res. 2004 Feb 1;64(3):1152-6. doi: 10.1158/0008-5472.can-03-2084. PMID:14871851 doi:http://dx.doi.org/10.1158/0008-5472.can-03-2084
- ↑ Salcedo R, Stauffer JK, Lincoln E, Back TC, Hixon JA, Hahn C, Shafer-Weaver K, Malyguine A, Kastelein R, Wigginton JM. IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors: role for CD8+ T cells. J Immunol. 2004 Dec 15;173(12):7170-82. doi: 10.4049/jimmunol.173.12.7170. PMID:15585838 doi:http://dx.doi.org/10.4049/jimmunol.173.12.7170
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- ↑ Villarino AV, Stumhofer JS, Saris CJ, Kastelein RA, de Sauvage FJ, Hunter CA. IL-27 limits IL-2 production during Th1 differentiation. J Immunol. 2006 Jan 1;176(1):237-47. doi: 10.4049/jimmunol.176.1.237. PMID:16365415 doi:http://dx.doi.org/10.4049/jimmunol.176.1.237
- ↑ Owaki T, Asakawa M, Kamiya S, Takeda K, Fukai F, Mizuguchi J, Yoshimoto T. IL-27 suppresses CD28-mediated [correction of medicated] IL-2 production through suppressor of cytokine signaling 3. J Immunol. 2006 Mar 1;176(5):2773-80. doi: 10.4049/jimmunol.176.5.2773. PMID:16493033 doi:http://dx.doi.org/10.4049/jimmunol.176.5.2773
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- ↑ Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D, Saris CJ, O'Shea JJ, Hennighausen L, Ernst M, Hunter CA. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol. 2006 Sep;7(9):937-45. doi: 10.1038/ni1376. Epub 2006 Aug 13. PMID:16906166 doi:http://dx.doi.org/10.1038/ni1376
- ↑ Batten M, Li J, Yi S, Kljavin NM, Danilenko DM, Lucas S, Lee J, de Sauvage FJ, Ghilardi N. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol. 2006 Sep;7(9):929-36. doi: 10.1038/ni1375. Epub 2006 Aug 13. PMID:16906167 doi:http://dx.doi.org/10.1038/ni1375
- ↑ Yoshimura T, Takeda A, Hamano S, Miyazaki Y, Kinjyo I, Ishibashi T, Yoshimura A, Yoshida H. Two-sided roles of IL-27: induction of Th1 differentiation on naive CD4+ T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4+ T cells partially through STAT3-dependent mechanism. J Immunol. 2006 Oct 15;177(8):5377-85. doi: 10.4049/jimmunol.177.8.5377. PMID:17015723 doi:http://dx.doi.org/10.4049/jimmunol.177.8.5377
- ↑ Owaki T, Asakawa M, Fukai F, Mizuguchi J, Yoshimoto T. IL-27 induces Th1 differentiation via p38 MAPK/T-bet- and intercellular adhesion molecule-1/LFA-1/ERK1/2-dependent pathways. J Immunol. 2006 Dec 1;177(11):7579-87. PMID:17114427
- ↑ Neufert C, Becker C, Wirtz S, Fantini MC, Weigmann B, Galle PR, Neurath MF. IL-27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1. Eur J Immunol. 2007 Jul;37(7):1809-16. doi: 10.1002/eji.200636896. PMID:17549733 doi:http://dx.doi.org/10.1002/eji.200636896
- ↑ Skladanowska K, Bloch Y, Strand J, White KF, Hua J, Aldridge D, Welin M, Logan DT, Soete A, Merceron R, Murphy C, Provost M, Bazan JF, Hunter CA, Hill JA, Savvides SN. Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27. Cell Rep. 2022 Oct 18;41(3):111490. doi: 10.1016/j.celrep.2022.111490. PMID:36261006 doi:http://dx.doi.org/10.1016/j.celrep.2022.111490
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