7zg0

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]}

See Also

• Interleukin 3D structures

References

1. ↑ Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, Hibbert L, Churakova T, Travis M, Vaisberg E, Blumenschein WM, Mattson JD, Wagner JL, To W, Zurawski S, McClanahan TK, Gorman DM, Bazan JF, de Waal Malefyt R, Rennick D, Kastelein RA. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity. 2002 Jun;16(6):779-90. doi: 10.1016/s1074-7613(02)00324-2. PMID:12121660 doi:http://dx.doi.org/10.1016/s1074-7613(02)00324-2
2. ↑ 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
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ Chiyo M, Shimozato O, Yu L, Kawamura K, Iizasa T, Fujisawa T, Tagawa M. Expression of IL-27 in murine carcinoma cells produces antitumor effects and induces protective immunity in inoculated host animals. Int J Cancer. 2005 Jun 20;115(3):437-42. doi: 10.1002/ijc.20848. PMID:15688376 doi:http://dx.doi.org/10.1002/ijc.20848
7. ↑ Morishima N, Owaki T, Asakawa M, Kamiya S, Mizuguchi J, Yoshimoto T. Augmentation of effector CD8+ T cell generation with enhanced granzyme B expression by IL-27. J Immunol. 2005 Aug 1;175(3):1686-93. doi: 10.4049/jimmunol.175.3.1686. PMID:16034109 doi:http://dx.doi.org/10.4049/jimmunol.175.3.1686
8. ↑ 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
9. ↑ 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
10. ↑ Shimizu M, Shimamura M, Owaki T, Asakawa M, Fujita K, Kudo M, Iwakura Y, Takeda Y, Luster AD, Mizuguchi J, Yoshimoto T. Antiangiogenic and antitumor activities of IL-27. J Immunol. 2006 Jun 15;176(12):7317-24. PMID:16751375
11. ↑ 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
12. ↑ 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
13. ↑ 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
14. ↑ 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
15. ↑ 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