Interleukin-27 (IL-27) is a cytokine with strikingly diverse influences on the immune response. Although it was initially linked with the development of Th1 responses, it is now recognized as a potent antagonist of different classes of inflammation through its ability to directly modify CD4+ and CD8+ T cell effector functions, to induce IL-10, and to promote specialized T regulatory cell responses. Although this aspect of IL-27 biology has provided insights into how the immune system prevents hyperactivity in the setting of infectious and autoimmune inflammation, in vaccination and cancer models the stimulatory effects of IL-27 on CD8+ T cell function appear prominent. Additionally, associations between IL-27 and antibody-mediated disease have led to an interest in defining the impact of IL-27 on innate immunity and humoral responses in different disease states. The maturation of this literature has been accompanied by attempts to translate these findings from experimental models into human diseases and by efforts to define where IL-27 might represent a viable therapeutic target.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H. 1.  et al. 2002. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16:779–90 [Google Scholar]
  2. Pflanz S, Hibbert L, Mattson J, Rosales R, Vaisberg E. 2.  et al. 2004. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immunol. 172:2225–31 [Google Scholar]
  3. Kastelein RA, Hunter CA, Cua DJ. 3.  2007. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25:221–42 [Google Scholar]
  4. Nieuwenhuis EE, Neurath MF, Corazza N, Iijima H, Trgovcich J. 4.  et al. 2002. Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice. PNAS 99:16951–56 [Google Scholar]
  5. Chen Q, Ghilardi N, Wang H, Baker T, Xie MH. 5.  et al. 2000. Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature 407:916–20 [Google Scholar]
  6. Yoshida H, Hamano S, Senaldi G, Covey T, Faggioni R. 6.  et al. 2001. WSX-1 is required for the initiation of Th1 responses and resistance to L. major infection. Immunity 15:569–78 [Google Scholar]
  7. Takeda A, Hamano S, Yamanaka A, Hanada T, Ishibashi T. 7.  et al. 2003. Cutting Edge: role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment. J. Immunol. 170:4886–90 [Google Scholar]
  8. Lucas S, Ghilardi N, Li J, de Sauvage FJ. 8.  2003. IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms. PNAS 100:15047–52 [Google Scholar]
  9. Villarino A, Hibbert L, Lieberman L, Wilson E, Mak T. 9.  et al. 2003. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity 19:645–55 [Google Scholar]
  10. Artis D, Johnson LM, Joyce K, Saris C, Villarino A. 10.  et al. 2004. Cutting Edge: early IL-4 production governs the requirement for IL-27-WSX-1 signaling in the development of protective Th1 cytokine responses following Leishmania major infection. J. Immunol. 172:4672–75 [Google Scholar]
  11. Hamano S, Himeno K, Miyazaki Y, Ishii K, Yamanaka A. 11.  et al. 2003. WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production. Immunity 19:657–67 [Google Scholar]
  12. Artis D, Villarino A, Silverman M, He W, Thornton EM. 12.  et al. 2004. The IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of type 2 immunity. J. Immunol. 173:5626–34 [Google Scholar]
  13. Holscher C, Holscher A, Ruckerl D, Yoshimoto T, Yoshida H. 13.  et al. 2005. The IL-27 receptor chain WSX-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis. J. Immunol. 174:3534–44 [Google Scholar]
  14. Rosas LE, Satoskar AA, Roth KM, Keiser TL, Barbi J. 14.  et al. 2006. Interleukin-27R (WSX-1/T-cell cytokine receptor) gene-deficient mice display enhanced resistance to Leishmania donovani infection but develop severe liver immunopathology. Am. J. Pathol. 168:158–69 [Google Scholar]
  15. Anderson CF, Stumhofer JS, Hunter CA, Sacks D. 15.  2009. IL-27 regulates IL-10 and IL-17 from CD4+ cells in nonhealing Leishmania major infection. J. Immunol. 183:4619–27 [Google Scholar]
  16. Robinson CM, Nau GJ. 16.  2008. Interleukin-12 and interleukin-27 regulate macrophage control of Mycobacterium tuberculosis. J. Infect. Dis. 198:359–66 [Google Scholar]
  17. de Aquino MT, Kapil P, Hinton DR, Phares TW, Puntambekar SS. 17.  et al. 2014. IL-27 limits central nervous system viral clearance by promoting IL-10 and enhances demyelination. J. Immunol. 193:285–94 [Google Scholar]
  18. Tirotta E, Duncker P, Oak J, Klaus S, Tsukamoto MR. 18.  et al. 2013. Epstein-Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis. J. Neuroimmunol. 254:110–16 [Google Scholar]
  19. Sun J, Dodd H, Moser EK, Sharma R, Braciale TJ. 19.  2011. CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs. Nat. Immunol. 12:327–34 [Google Scholar]
  20. Liu FD, Kenngott EE, Schroter MF, Kuhl A, Jennrich S. 20.  et al. 2014. Timed action of IL-27 protects from immunopathology while preserving defense in influenza. PLOS Pathog. 10:e1004110 [Google Scholar]
  21. Findlay EG, Greig R, Stumhofer JS, Hafalla JC, de Souza JB. 21.  et al. 2011. Essential role for IL-27 receptor signaling in prevention of Th1-mediated immunopathology during malaria infection. J. Immunol. 185:2482–92 [Google Scholar]
  22. Batten M, Kljavin NM, Li J, Walter MJ, de Sauvage FJ, Ghilardi N. 22.  2008. Cutting Edge: IL-27 is a potent inducer of IL-10 but not FoxP3 in murine T Cells. J. Immunol. 180:2752–56 [Google Scholar]
  23. Yang J, Yang M, Htut TM, Ouyang X, Hanidu A. 23.  et al. 2008. Epstein-Barr virus-induced gene 3 negatively regulates IL-17, IL-22 and RORγt. Eur. J. Immunol. 38:1204–14 [Google Scholar]
  24. Shimizu S, Sugiyama N, Masutani K, Sadanaga A, Miyazaki Y. 24.  et al. 2005. Membranous glomerulonephritis development with Th2-type immune deviations in MRL/lpr mice deficient for IL-27 receptor (WSX-1). J. Immunol. 175:7185–92 [Google Scholar]
  25. Batten M, Li J, Yi S, Kljavin NM, Danilenko DM. 25.  et al. 2006. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat. Immunol. 7:929–36 [Google Scholar]
  26. Troy AE, Zaph C, Du Y, Taylor BC, Guild KJ. 26.  et al. 2009. IL-27 regulates homeostasis of the intestinal CD4+ effector T cell pool and limits intestinal inflammation in a murine model of colitis. J. Immunol. 183:2037–44 [Google Scholar]
  27. Igawa T, Nakashima H, Sadanaga A, Masutani K, Miyake K. 27.  et al. 2009. Deficiency in EBV-induced gene 3 (EBI3) in MRL/lpr mice results in pathological alteration of autoimmune glomerulonephritis and sialadenitis. Mod. Rheumatol. 19:33–41 [Google Scholar]
  28. Yoshimoto T, Yasuda K, Mizuguchi J, Nakanishi K. 28.  2007. IL-27 suppresses Th2 cell development and Th2 cytokines production from polarized Th2 cells: a novel therapeutic way for Th2-mediated allergic inflammation. J. Immunol. 179:4415–23 [Google Scholar]
  29. Diveu C, McGeachy MJ, Boniface K, Stumhofer JS, Sathe M. 29.  et al. 2009. IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. J. Immunol. 182:5748–56 [Google Scholar]
  30. Yamanaka A, Hamano S, Miyazaki Y, Ishii K, Takeda A. 30.  et al. 2004. Hyperproduction of proinflammatory cytokines by WSX-1-deficient NKT cells in concanavalin A-induced hepatitis. J. Immunol. 172:3590–96 [Google Scholar]
  31. Zhang S, Liang R, Luo W, Liu C, Wu X. 31.  et al. 2013. High susceptibility to liver injury in IL-27 p28 conditional knockout mice involves intrinsic interferon-γ dysregulation of CD4+ T cells. Hepatology 57:1620–31 [Google Scholar]
  32. Kim G, Shinnakasu R, Saris CJ, Cheroutre H, Kronenberg M. 32.  2013. A novel role for IL-27 in mediating the survival of activated mouse CD4 T lymphocytes. J. Immunol. 190:1510–18 [Google Scholar]
  33. Devergne O, Hummel M, Koeppen H, Le Beau MM, Nathnson EC. 33.  et al. 1996. A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes. J. Virol. 70:1143–53 [Google Scholar]
  34. Devergne O, Birkenbach M, Kieff E. 34.  1997. Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. PNAS 94:12041–46 [Google Scholar]
  35. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y. 35.  et al. 2007. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450:566–69 [Google Scholar]
  36. Crabe S, Guay-Giroux A, Tormo AJ, Duluc D, Lissilaa R. 36.  et al. 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. J. Immunol. 183:7692–702 [Google Scholar]
  37. Wang RX, Yu CR, Mahdi RM, Egwuagu CE. 37.  2012. Novel IL27p28/IL12p40 cytokine suppressed experimental autoimmune uveitis by inhibiting autoreactive Th1/Th17 cells and promoting expansion of regulatory T cells. J. Biol. Chem. 287:36012–21 [Google Scholar]
  38. Stumhofer JS, Tait ED, Quinn WJ III, Hosken N, Spudy B. 38.  et al. 2010. A role for IL-27p28 as an antagonist of gp130-mediated signaling. Nat. Immunol. 11:1119–26 [Google Scholar]
  39. Shimozato O, Sato A, Kawamura K, Chiyo M, Ma G. 39.  et al. 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:e816–25 [Google Scholar]
  40. Dibra D, Cutrera J, Xia X, Kallakury B, Mishra L, Li S. 40.  2012. Interleukin-30: a novel antiinflammatory cytokine candidate for prevention and treatment of inflammatory cytokine-induced liver injury. Hepatology 55:1204–14 [Google Scholar]
  41. Rousseau F, Basset L, Froger J, Dinguirard N, Chevalier S, Gascan H. 41.  2010. IL-27 structural analysis demonstrates similarities with ciliary neurotrophic factor (CNTF) and leads to the identification of antagonistic variants. PNAS 107:19420–25 [Google Scholar]
  42. Garbers C, Spudy B, Aparicio-Siegmund S, Waetzig GH, Sommer J. 42.  et al. 2013. An interleukin-6 receptor-dependent molecular switch mediates signal transduction of the IL-27 cytokine subunit p28 (IL-30) via a gp130 protein receptor homodimer. J. Biol. Chem. 288:4346–54 [Google Scholar]
  43. Hall AO, Silver JS, Hunter CA. 43.  2012. The immunobiology of IL-27. Adv. Immunol. 115:1–44 [Google Scholar]
  44. Curran MA, Geiger TL, Montalvo W, Kim M, Reiner SL. 44.  et al. 2013. Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin. J. Exp. Med. 210:743–55 [Google Scholar]
  45. Dibra D, Cutrera JJ, Li S. 45.  2012. Coordination between TLR9 signaling in macrophages and CD3 signaling in T cells induces robust expression of IL-30. J. Immunol. 188:3709–15 [Google Scholar]
  46. van Seventer JM, Nagai T, van Seventer GA. 46.  2002. Interferon-β differentially regulates expression of the IL-12 family members p35, p40, p19 and EBI3 in activated human dendritic cells. J. Neuroimmunol. 133:60–71 [Google Scholar]
  47. Remoli ME, Gafa V, Giacomini E, Severa M, Lande R, Coccia EM. 47.  2007. IFN-β modulates the response to TLR stimulation in human DC: Involvement of IFN regulatory factor-1 (IRF-1) in IL-27 gene expression. Eur. J. Immunol. 37:3499–508 [Google Scholar]
  48. Molle C, Nguyen M, Flamand V, Renneson J, Trottein F. 48.  et al. 2007. IL-27 synthesis induced by TLR ligation critically depends on IFN regulatory factor 3. J. Immunol. 178:7607–15 [Google Scholar]
  49. Liu J, Guan X, Ma X. 49.  2007. Regulation of IL-27 p28 gene expression in macrophages through MyD88- and interferon-γ -mediated pathways. J. Exp. Med. 204:141–52 [Google Scholar]
  50. Pirhonen J, Siren J, Julkunen I, Matikainen S. 50.  2007. IFN-α regulates Toll-like receptor-mediated IL-27 gene expression in human macrophages. J. Leukoc. Biol. 82:1185–92 [Google Scholar]
  51. Bosmann M, Ward PA. 51.  2013. Modulation of inflammation by interleukin-27. J. Leukoc. Biol. 94:1159–65 [Google Scholar]
  52. Schnurr M, Toy T, Shin A, Wagner M, Cebon J, Maraskovsky E. 52.  2005. Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway. Blood 105:1582–89 [Google Scholar]
  53. Hawlisch H, Belkaid Y, Baelder R, Hildeman D, Gerard C, Kohl J. 53.  2005. C5a negatively regulates Toll-like receptor 4-induced immune responses. Immunity 22:415–26 [Google Scholar]
  54. Sala A, Gadina M, Kelsall BL. 54.  la 2005. Gi-protein-dependent inhibition of IL-12 production is mediated by activation of the phosphatidylinositol 3-kinase-protein 3 kinase B/Akt pathway and JNK. J. Immunol. 175:2994–99 [Google Scholar]
  55. Bosmann M, Haggadone MD, Hemmila MR, Zetoune FS, Sarma JV, Ward PA. 55.  2012. Complement activation product C5a is a selective suppressor of TLR4-induced, but not TLR3-induced, production of IL-27(p28) from macrophages. J. Immunol. 188:5086–93 [Google Scholar]
  56. Pawaria S, Ramani K, Maers K, Liu Y, Kane LP. 56.  et al. 2014. Complement component C5a permits the coexistence of pathogenic Th17 Cells and type I IFN in lupus. J. Immunol. 193:3179–80 [Google Scholar]
  57. Lambert QT, Pradhan A, Roll JD, Reuther GW. 57.  2011. Mutations in the transmembrane and juxtamembrane domains enhance IL27R transforming activity. Biochem. J. 438:155–64 [Google Scholar]
  58. Pradhan A, Lambert QT, Reuther GW. 58.  2007. Transformation of hematopoietic cells and activation of JAK2-V617F by IL-27R, a component of a heterodimeric type I cytokine receptor. PNAS 104:18502–7 [Google Scholar]
  59. Sprecher CA, Grant FJ, Baumgartner JW, Presnell SR, Schrader SK. 59.  et al. 1998. Cloning and characterization of a novel class I cytokine receptor. Biochem. Biophys. Res. Commun. 246:82–90 [Google Scholar]
  60. Perona-Wright G, Kohlmeier JE, Bassity E, Freitas TC, Mohrs K. 60.  et al. 2012. Persistent loss of IL-27 responsiveness in CD8+ memory T cells abrogates IL-10 expression in a recall response. PNAS 109:18535–40 [Google Scholar]
  61. Hashimoto Y, Kurita M, Aiso S, Nishimoto I, Matsuoka M. 61.  2009. Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor α/WSX-1/gp130. Mol. Biol. Cell 20:2864–73 [Google Scholar]
  62. Collison LW, Delgoffe GM, Guy CS, Vignali KM, Chaturvedi V. 62.  et al. 2012. The composition and signaling of the IL-35 receptor are unconventional. Nat. Immunol. 13:290–99 [Google Scholar]
  63. Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB. 63.  et al. 2014. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat. Med. 20:633–41 [Google Scholar]
  64. Dietrich C, Candon S, Ruemmele FM, Devergne O. 64.  2014. A soluble form of IL-27Rα is a natural IL-27 antagonist. J. Immunol. 192:5382–89 [Google Scholar]
  65. Levin AM, Bates DL, Ring AM, Krieg C, Lin JT. 65.  et al. 2012. Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature 484:529–33 [Google Scholar]
  66. Villarino AV, Stumhofer JS, Saris CJ, Kastelein RA, de Sauvage FJ, Hunter CA. 66.  2006. IL-27 limits IL-2 production during Th1 differentiation. J. Immunol. 176:237–47 [Google Scholar]
  67. Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM. 67.  et al. 2006. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7:937–45 [Google Scholar]
  68. Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH. 68.  et al. 2007. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 8:1363–71 [Google Scholar]
  69. Hall AO, Beiting DP, Tato C, John B, Oldenhove G. 69.  et al. 2012. The cytokines interleukin 27 and interferon-γ promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37:511–23 [Google Scholar]
  70. Young A, Linehan E, Hams E, O'Hara Hall AC, McClurg A. 70.  et al. 2012. Cutting Edge: suppression of GM-CSF expression in murine and human T cells by IL-27. J. Immunol. 189:2079–83 [Google Scholar]
  71. Bancroft AJ, Humphreys NE, Worthington JJ, Yoshida H, Grencis RK. 71.  2004. WSX-1: a key role in induction of chronic intestinal nematode infection. J. Immunol. 172:7635–41 [Google Scholar]
  72. Villarino AV, Artis D, Bezbradica JS, Miller O, Saris CJ. 72.  et al. 2008. IL-27R deficiency delays the onset of colitis and protects from helminth-induced pathology in a model of chronic IBD. Int. Immunol. 20:739–52 [Google Scholar]
  73. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T. 73.  et al. 2003. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198:1951–57 [Google Scholar]
  74. Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S. 74.  et al. 2012. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13:991–99 [Google Scholar]
  75. El-behi M, Ciric B, Yu S, Zhang GX, Fitzgerald DC, Rostami A. 75.  2009. Differential effect of IL-27 on developing versus committed Th17 cells. J. Immunol. 183:4957–67 [Google Scholar]
  76. Murugaiyan G, Mittal A, Lopez-Diego R, Maier LM, Anderson DE, Weiner HL. 76.  2009. IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J. Immunol. 183:2435–43 [Google Scholar]
  77. Liu H, Rohowsky-Kochan C. 77.  2011. Interleukin-27-mediated suppression of human Th17 cells is associated with activation of STAT1 and suppressor of cytokine signaling protein 1. J. Interferon Cytokine Res. 31:459–69 [Google Scholar]
  78. Villarino AV, Gallo E, Abbas AK. 78.  2010. STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and -independent mechanisms. J. Immunol. 185:6461–71 [Google Scholar]
  79. Hirahara K, Ghoreschi K, Yang XP, Takahashi H, Laurence A. 79.  et al. 2012. Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1. Immunity 36:1017–30 [Google Scholar]
  80. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP. 80.  et al. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–87 [Google Scholar]
  81. Topalian SL, Drake CG, Pardoll DM. 81.  2012. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 24:207–12 [Google Scholar]
  82. Couper KN, Blount DG, Riley EM. 82.  2008. IL-10: the master regulator of immunity to infection. J. Immunol. 180:5771–77 [Google Scholar]
  83. Berg DJ, Davidson N, Kuhn R, Muller W, Menon S. 83.  et al. 1996. Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4+ TH1-like responses. J. Clin. Investig. 98:1010–20 [Google Scholar]
  84. Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M. 84.  et al. 2007. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat. Immunol. 8:1380–89 [Google Scholar]
  85. Fitzgerald DC, Zhang GX, El-Behi M, Fonseca-Kelly Z, Li H. 85.  et al. 2007. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat. Immunol. 8:1372–79 [Google Scholar]
  86. Freitas do Rosario AP, Lamb T, Spence P, Stephens R, Lang A. 86.  et al. 2012. IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. J. Immunol. 188:1178–90 [Google Scholar]
  87. Ansari NA, Kumar R, Gautam S, Nylen S, Singh OP. 87.  et al. 2011. IL-27 and IL-21 are associated with T cell IL-10 responses in human visceral leishmaniasis. J. Immunol. 186:3977–85 [Google Scholar]
  88. Wang H, Meng R, Li Z, Yang B, Liu Y. 88.  et al. 2011. IL-27 induces the differentiation of Tr1-like cells from human naive CD4+ T cells via the phosphorylation of STAT1 and STAT3. Immunol. Lett. 136:21–28 [Google Scholar]
  89. Pot C, Jin H, Awasthi A, Liu SM, Lai CY. 89.  et al. 2009. Cutting Edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J. Immunol. 183:797–801 [Google Scholar]
  90. Xu J, Yang Y, Qiu G, Lal G, Wu Z. 90.  et al. 2009. c-Maf regulates IL-10 expression during Th17 polarization. J. Immunol. 182:6226–36 [Google Scholar]
  91. Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S. 91.  et al. 2010. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 11:854–61 [Google Scholar]
  92. Stumhofer JS, Silver JS, Hunter CA. 92.  2013. IL-21 is required for optimal antibody production and T cell responses during chronic Toxoplasma gondii infection. PLOS ONE 8:e62889 [Google Scholar]
  93. Wu C, Pot C, Apetoh L, Thalhamer T, Zhu B. 93.  et al. 2013. Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation. PNAS 110:7802–7 [Google Scholar]
  94. Seita J, Asakawa M, Ooehara J, Takayanagi S, Morita Y. 94.  et al. 2008. Interleukin-27 directly induces differentiation in hematopoietic stem cells. Blood 111:1903–12 [Google Scholar]
  95. Wojno ED, Hosken N, Stumhofer JS, O'Hara AC, Mauldin E. 95.  et al. 2011. A role for IL-27 in limiting T regulatory cell populations. J. Immunol. 187:266–73 [Google Scholar]
  96. Neufert C, Becker C, Wirtz S, Fantini MC, Weigmann B. 96.  et al. 2007. IL-27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1. Eur. J. Immunol. 37:1809–16 [Google Scholar]
  97. Huber M, Steinwald V, Guralnik A, Brustle A, Kleemann P. 97.  et al. 2008. IL-27 inhibits the development of regulatory T cells via STAT3. Int. Immunol. 20:223–34 [Google Scholar]
  98. Cox JH, Kljavin NM, Ramamoorthi N, Diehl L, Batten M, Ghilardi N. 98.  2011. IL-27 promotes T cell-dependent colitis through multiple mechanisms. J. Exp. Med. 208:115–23 [Google Scholar]
  99. Villarino AV, Larkin J 3rd, Saris CJ, Caton AJ, Lucas S. 99.  et al. 2005. Positive and negative regulation of the IL-27 receptor during lymphoid cell activation. J. Immunol. 174:7684–91 [Google Scholar]
  100. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. 100.  2009. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10:595–602 [Google Scholar]
  101. Oldenhove G, Bouladoux N, Wohlfert EA, Hall JA, Chou D. 101.  et al. 2009. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31:772–86 [Google Scholar]
  102. Moon SJ, Park JS, Heo YJ, Kang CM, Kim EK. 102.  et al. 2013. In vivo action of IL-27: reciprocal regulation of Th17 and Treg cells in collagen-induced arthritis. Exp. Mol. Med. 45:e46 [Google Scholar]
  103. Owaki T, Asakawa M, Fukai F, Mizuguchi J, Yoshimoto T. 103.  2006. IL-27 Induces Th1 differentiation via p38 MAPK/T-bet- and intercellular adhesion molecule-1/LFA-1/ERK1/2-dependent pathways. J. Immunol. 177:7579–87 [Google Scholar]
  104. Liao JJ, Huang MC, Goetzl EJ. 104.  2007. Cutting Edge: alternative signaling of Th17 cell development by sphingosine 1-phosphate. J. Immunol. 178:5425–28 [Google Scholar]
  105. Gwyer Findlay E, Villegas-Mendez A, de Souza JB, Inkson CA, Shaw TN. 105.  et al. 2013. IL-27 receptor signaling regulates CD4+ T cell chemotactic responses during infection. J. Immunol. 190:4553–61 [Google Scholar]
  106. Morishima N, Owaki T, Asakawa M, Kamiya S, Mizuguchi J, Yoshimoto T. 106.  2005. Augmentation of effector CD8+ T cell generation with enhanced granzyme B expression by IL-27. J. Immunol. 175:1686–93 [Google Scholar]
  107. Schneider R, Yaneva T, Beauseigle D, El-Khoury L, Arbour N. 107.  2011. IL-27 increases the proliferation and effector functions of human naive CD8+ T lymphocytes and promotes their development into Tc1 cells. Eur. J. Immunol. 41:47–59 [Google Scholar]
  108. Brender C, Tannahill GM, Jenkins BJ, Fletcher J, Columbus R. 108.  et al. 2007. Suppressor of cytokine signaling 3 regulates CD8 T-cell proliferation by inhibition of interleukins 6 and 27. Blood 110:2528–36 [Google Scholar]
  109. Chiyo M, Shimozato O, Yu L, Kawamura K, Iizasa T. 109.  et al. 2005. Expression of IL-27 in murine carcinoma cells produces antitumor effects and induces protective immunity in inoculated host animals. Int. J. Cancer 115:437–42 [Google Scholar]
  110. Chiyo M, Shimozato O, Iizasa T, Fujisawa T, Tagawa M. 110.  2004. Antitumor effects produced by transduction of dendritic cells-derived heterodimeric cytokine genes in murine colon carcinoma cells. Anticancer Res. 24:3763–67 [Google Scholar]
  111. Hisada M, Kamiya S, Fujita K, Belladonna ML, Aoki T. 111.  et al. 2004. Potent antitumor activity of interleukin-27. Cancer Res. 64:1152–56 [Google Scholar]
  112. Salcedo R, Hixon JA, Stauffer JK, Jalah R, Brooks AD. 112.  et al. 2009. Immunologic and therapeutic synergy of IL-27 and IL-2: enhancement of T cell sensitization, tumor-specific CTL reactivity and complete regression of disseminated neuroblastoma metastases in the liver and bone marrow. J. Immunol. 182:4328–38 [Google Scholar]
  113. Salcedo R, Stauffer JK, Lincoln E, Back TC, Hixon JA. 113.  et al. 2004. IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors: role for CD8+ T cells. J. Immunol. 173:7170–82 [Google Scholar]
  114. Shinozaki Y, Wang S, Miyazaki Y, Miyazaki K, Yamada H. 114.  et al. 2009. Tumor-specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti-tumor immunity. Int. J. Cancer 124:1372–78 [Google Scholar]
  115. Mayer KD, Mohrs K, Reiley W, Wittmer S, Kohlmeier JE. 115.  et al. 2008. Cutting Edge: T-bet and IL-27R are critical for in vivo IFN-γ production by CD8 T cells during infection. J. Immunol. 180:693–97 [Google Scholar]
  116. Pennock ND, Gapin L, Kedl RM. 116.  2014. IL-27 is required for shaping the magnitude, affinity distribution and memory of T cells responding to subunit immunization. PNAS 111:16472–77 [Google Scholar]
  117. Biswas PS, Pedicord V, Ploss A, Menet E, Leiner I, Pamer EG. 117.  2007. Pathogen-specific CD8 T cell responses are directly inhibited by IL-10. J. Immunol. 179:4520–28 [Google Scholar]
  118. Foulds KE, Rotte MJ, Seder RA. 118.  2006. IL-10 is required for optimal CD8 T cell memory following Listeria monocytogenes infection. J. Immunol. 177:2565–74 [Google Scholar]
  119. Villarino AV, Tato CM, Stumhofer JS, Yao Z, Cui YK. 119.  et al. 2007. Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals. J. Exp. Med. 204:65–71 [Google Scholar]
  120. Trinchieri G. 120.  2003. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3:133–46 [Google Scholar]
  121. Villarino AV, Huang E, Hunter CA. 121.  2004. Understanding the pro- and anti-inflammatory properties of IL-27. J. Immunol. 173:715–20 [Google Scholar]
  122. Miyazaki Y, Inoue H, Matsumura M, Matsumoto K, Nakano T. 122.  et al. 2005. Exacerbation of experimental allergic asthma by augmented Th2 responses in WSX-1-deficient mice. J. Immunol. 175:2401–7 [Google Scholar]
  123. Artis D, Johnson LM, Joyce K, Saris C, Villarino A. 123.  et al. 2004. Cutting Edge: early IL-4 production governs the requirement for IL-27-WSX-1 signaling in the development of protective Th1 cytokine responses following Leishmania major infection. J. Immunol. 172:4672–75 [Google Scholar]
  124. Miyazaki Y, Inoue H, Matsumura M, Matsumoto K, Nakano T. 124.  et al. 2005. Exacerbation of experimental allergic asthma by augmented Th2 responses in WSX-1-deficient mice. J. Immunol. 175:2401–7 [Google Scholar]
  125. Harker JA, Lewis GM, Mack L, Zuniga EI. 125.  2012. Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. Science 334:825–29 [Google Scholar]
  126. Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho IC. 126.  et al. 2009. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat. Immunol. 10:167–75 [Google Scholar]
  127. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS. 127.  et al. 2008. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29:138–49 [Google Scholar]
  128. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J. 128.  et al. 2002. A critical role for IL-21 in regulating immunoglobulin production. Science 298:1630–34 [Google Scholar]
  129. Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G. 129.  et al. 2004. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J. Immunol. 173:5361–71 [Google Scholar]
  130. Cao Y, Doodes PD, Glant TT, Finnegan A. 130.  2008. IL-27 induces a Th1 immune response and susceptibility to experimental arthritis. J. Immunol. 180:922–30 [Google Scholar]
  131. Batten M, Ramamoorthi N, Kljavin NM, Ma CS, Cox JH. 131.  et al. 2010. IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells. J. Exp. Med. 207:2895–906 [Google Scholar]
  132. Harker JA, Dolgoter A, Zuniga EI. 132.  2013. Cell-intrinsic IL-27 and gp130 cytokine receptor signaling regulates virus-specific CD4+ T cell responses and viral control during chronic infection. Immunity 39:548–59 [Google Scholar]
  133. Ballesteros-Tato A, Leon B, Graf BA, Moquin A, Adams PS. 133.  et al. 2012. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36:847–56 [Google Scholar]
  134. Johnston RJ, Choi YS, Diamond JA, Yang JA, Crotty S. 134.  2012. STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209:243–50 [Google Scholar]
  135. Nurieva RI, Podd A, Chen Y, Alekseev AM, Yu M. 135.  et al. 2012. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J. Biol. Chem. 287:11234–39 [Google Scholar]
  136. Boumendjel A, Tawk L, de Waal Malefijt R, Boulay V, Yssel H, Pène J. 136.  2006. IL-27 induces the production of IgG1 by human B cells. Eur. Cytokine Netw. 17:281–89 [Google Scholar]
  137. Yoshimoto T, Okada K, Morishima N, Kamiya S, Owaki T. 137.  et al. 2004. Induction of IgG2a class switching in B cells by IL-27. J. Immunol. 173:2479–85 [Google Scholar]
  138. Larousserie F, Charlot P, Bardel E, Froger J, Kastelein RA, Devergne O. 138.  2006. Differential effects of IL-27 on human B cell subsets. J. Immunol. 176:5890–97 [Google Scholar]
  139. Charlot-Rabiega P, Bardel E, Dietrich C, Kastelein R, Devergne O. 139.  2011. Signaling events involved in interleukin 27 (IL-27)-induced proliferation of human naive CD4+ T cells and B cells. J. Biol. Chem. 286:27350–62 [Google Scholar]
  140. Cocco C, Morandi F, Airoldi I. 140.  2011. Interleukin-27 and interleukin-23 modulate human plasmacell functions. J. Leukoc. Biol. 89:729–34 [Google Scholar]
  141. Doreau A, Belot A, Bastid J, Riche B, Trescol-Biemont MC. 141.  et al. 2009. Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat. Immunol. 10:778–85 [Google Scholar]
  142. Dibra D, Cutrera JJ, Xia X, Birkenbach MP, Li S. 142.  2009. Expression of WSX1 in tumors sensitizes IL-27 signaling-independent natural killer cell surveillance. Cancer Res. 69:5505–13 [Google Scholar]
  143. Dibra D, Cutrera J, Xia X, Li S. 143.  2011. WSX1 expression in tumors induces immune tolerance via suppression of effector immune cells. PLOS ONE 6:e19072 [Google Scholar]
  144. Yoshimoto T, Morishima N, Mizoguchi I, Shimizu M, Nagai H. 144.  et al. 2008. Antiproliferative activity of IL-27 on melanoma. J. Immunol. 180:6527–35 [Google Scholar]
  145. Dong S, Zhang X, He Y, Xu F, Li D. 145.  et al. 2013. Synergy of IL-27 and TNF-α in regulating CXCL10 expression in lung fibroblasts. Am. J. Respir. Cell Mol. Biol. 48:518–30 [Google Scholar]
  146. Hu S, Wong CK, Lam CW. 146.  2011. Activation of eosinophils by IL-12 family cytokine IL-27: implications of the pleiotropic roles of IL-27 in allergic responses. Immunobiology 216:54–65 [Google Scholar]
  147. Kido M, Takeuchi S, Sugiyama N, Esaki H, Nakashima H. 147.  et al. 2011. T cell-specific overexpression of interleukin-27 receptor α subunit (WSX-1) prevents spontaneous skin inflammation in MRL/lpr mice. Br. J. Dermatol. 164:1214–20 [Google Scholar]
  148. Wirtz S, Tubbe I, Galle PR, Schild HJ, Birkenbach M. 148.  et al. 2006. Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27. J. Exp. Med. 203:1875–81 [Google Scholar]
  149. de Almeida Nagata DE, Demoor T, Ptaschinski C, Ting HA, Jang S. 149.  et al. 2014. IL-27R-mediated regulation of IL-17 controls the development of respiratory syncytial virus-associated pathogenesis. Am. J. Pathol. 184:1807–18 [Google Scholar]
  150. Zeng R, Zhang H, Hai Y, Cui Y, Wei L. 150.  et al. 2012. Interleukin-27 inhibits vaccine-enhanced pulmonary disease following respiratory syncytial virus infection by regulating cellular memory responses. J. Virol. 86:4505–17 [Google Scholar]
  151. Passos ST, Silver JS, O'Hara AC, Sehy D, Stumhofer JS, Hunter CA. 151.  2010. IL-6 promotes NK cell production of IL-17 during toxoplasmosis. J. Immunol. 184:1776–83 [Google Scholar]
  152. Cao J, Wang D, Xu F, Gong Y, Wang H. 152.  et al. 2014. Activation of IL-27 signalling promotes development of postinfluenza pneumococcal pneumonia. EMBO Mol. Med. 6:120–40 [Google Scholar]
  153. Laroni A, Gandhi R, Beynon V, Weiner HL. 153.  2011. IL-27 imparts immunoregulatory function to human NK cell subsets. PLOS ONE 6:e26173 [Google Scholar]
  154. Wei J, Xia S, Sun H, Zhang S, Wang J. 154.  et al. 2013. Critical role of dendritic cell-derived IL-27 in antitumor immunity through regulating the recruitment and activation of NK and NKT cells. J. Immunol. 191:500–8 [Google Scholar]
  155. Wang S, Miyazaki Y, Shinozaki Y, Yoshida H. 155.  2007. Augmentation of antigen-presenting and Th1-promoting functions of dendritic cells by WSX-1(IL-27R) deficiency. J. Immunol. 179:6421–28 [Google Scholar]
  156. Mascanfroni ID, Yeste A, Vieira SM, Burns EJ, Patel B. 156.  et al. 2013. IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39. Nat. Immunol. 14:1054–63 [Google Scholar]
  157. Karakhanova S, Bedke T, Enk AH, Mahnke K. 157.  2011. IL-27 renders DC immunosuppressive by induction of B7-H1. J. Leukoc. Biol. 89:837–45 [Google Scholar]
  158. Morandi F, Di Carlo E, Ferrone S, Petretto A, Pistoia V, Airoldi I. 158.  2014. IL-27 in human secondary lymphoid organs attracts myeloid dendritic cells and impairs HLA class I-restricted antigen presentation. J. Immunol. 192:2634–42 [Google Scholar]
  159. Kalliolias GD, Ivashkiv LB. 159.  2008. IL-27 activates human monocytes via STAT1 and suppresses IL-10 production but the inflammatory functions of IL-27 are abrogated by TLRs and p38. J. Immunol. 180:6325–33 [Google Scholar]
  160. Iyer SS, Ghaffari AA, Cheng G. 160.  2010. Lipopolysaccharide-mediated IL-10 transcriptional regulation requires sequential induction of type I IFNs and IL-27 in macrophages. J. Immunol. 185:6599–607 [Google Scholar]
  161. Imamichi T, Yang J, Huang DW, Brann TW, Fullmer BA. 161.  et al. 2008. IL-27, a novel anti-HIV cytokine, activates multiple interferon-inducible genes in macrophages. AIDS 22:39–45 [Google Scholar]
  162. Dai L, Lidie KB, Chen Q, Adelsberger JW, Zheng X. 162.  et al. 2013. IL-27 inhibits HIV-1 infection in human macrophages by down-regulating host factor SPTBN1 during monocyte to macrophage differentiation. J. Exp. Med. 210:517–34 [Google Scholar]
  163. Cao Y, Zhang R, Zhang W, Zhu C, Yu Y. 163.  et al. 2014. IL-27, a cytokine, and IFN-λ1, a type III IFN, are coordinated to regulate virus replication through type I IFN. J. Immunol. 192:691–703 [Google Scholar]
  164. Liu L, Cao Z, Chen J, Li R, Cao Y. 164.  et al. 2012. Influenza A virus induces interleukin-27 through cyclooxygenase-2 and protein kinase A signaling. J. Biol. Chem. 287:11899–910 [Google Scholar]
  165. Swaminathan S, Hu X, Zheng X, Kriga Y, Shetty J. 165.  et al. 2013. Interleukin-27 treated human macrophages induce the expression of novel microRNAs which may mediate anti-viral properties. Biochem. Biophys. Res. Commun. 434:228–34 [Google Scholar]
  166. Kalliolias GD, Gordon RA, Ivashkiv LB. 166.  2010. Suppression of TNF-α and IL-1 signaling identifies a mechanism of homeostatic regulation of macrophages by IL-27. J. Immunol. 185:7047–56 [Google Scholar]
  167. Jafarzadeh A, Nemati M, Rezayati MT. 167.  2011. Serum levels of interleukin (IL)-27 in patients with ischemic heart disease. Cytokine 56:153–56 [Google Scholar]
  168. Wong HR, Cvijanovich NZ, Hall M, Allen GL, Thomas NJ. 168.  et al. 2012. Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children. Crit. Care 16:R213 [Google Scholar]
  169. Wong HR, Lindsell CJ, Lahni P, Hart KW, Gibot S. 169.  2013. Interleukin 27 as a sepsis diagnostic biomarker in critically ill adults. Shock 40:382–86 [Google Scholar]
  170. Du HZ, Wang Q, Ji J, Shen BM, Wei SC. 170.  et al. 2013. Expression of IL-27, Th1 and Th17 in patients with aplastic anemia. J. Clin. Immunol. 33:436–45 [Google Scholar]
  171. Lin TT, Lu J, Qi CY, Yuan L, Li XL. 171.  et al. 2014. Elevated serum level of IL-27 and VEGF in patients with ankylosing spondylitis and associate with disease activity. Clin. Exp. Med. In press. doi: 10.1007/s10238-014-0281-x [Google Scholar]
  172. Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL. 172.  et al. 2007. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat. Med. 13:711–18 [Google Scholar]
  173. Karp CL, el-Safi SH, Wynn TA, Satti MM, Kordofani AM. 173.  et al. 1993. In vivo cytokine profiles in patients with kala-azar. Marked elevation of both interleukin-10 and interferon-γ. J. Clin. Investig. 91:1644–48 [Google Scholar]
  174. Gautam S, Kumar R, Maurya R, Nylen S, Ansari N. 174.  et al. 2011. IL-10 neutralization promotes parasite clearance in splenic aspirate cells from patients with visceral leishmaniasis. J. Infect. Dis. 204:1134–37 [Google Scholar]
  175. Ayimba E, Hegewald J, Segbena AY, Gantin RG, Lechner CJ. 175.  et al. 2011. Proinflammatory and regulatory cytokines and chemokines in infants with uncomplicated and severe Plasmodium falciparum malaria. Clin. Exp. Immunol. 166:218–26 [Google Scholar]
  176. Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S. 176.  et al. 2011. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med. 208:1635–48 [Google Scholar]
  177. Sonobe Y, Yawata I, Kawanokuchi J, Takeuchi H, Mizuno T, Suzumura A. 177.  2005. Production of IL-27 and other IL-12 family cytokines by microglia and their subpopulations. Brain Res. 1040:202–7 [Google Scholar]
  178. Fitzgerald DC, Ciric B, Touil T, Harle H, Grammatikopolou J. 178.  et al. 2007. Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J. Immunol. 179:3268–75 [Google Scholar]
  179. Murugaiyan G, Beynon V, Pires Da Cunha A, Joller N, Weiner HL. 179.  2012. IFN-γ limits Th9-mediated autoimmune inflammation through dendritic cell modulation of IL-27. J. Immunol. 189:5277–83 [Google Scholar]
  180. Pirhonen J, Siren J, Julkunen I, Matikainen S. 180.  2007. IFN-α regulates Toll-like receptor-mediated IL-27 gene expression in human macrophages. J. Leukoc. Biol. 82:1185–92 [Google Scholar]
  181. Guo B, Chang EY, Cheng G. 181.  2008. The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J. Clin. Investig. 118:1680–90 [Google Scholar]
  182. Shinohara ML, Kim JH, Garcia VA, Cantor H. 182.  2008. Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin. Immunity 29:68–78 [Google Scholar]
  183. Sweeney CM, Lonergan R, Basdeo SA, Kinsella K, Dungan LS. 183.  et al. 2011. IL-27 mediates the response to IFN-β therapy in multiple sclerosis patients by inhibiting Th17 cells. Brain Behav. Immun. 25:1170–81 [Google Scholar]
  184. Niedbala W, Cai B, Wei X, Patakas A, Leung BP. 184.  et al. 2008. Interleukin-27 attenuates collagen-induced arthritis. Ann. Rheum. Dis. 67:1474–79 [Google Scholar]
  185. Pickens SR, Chamberlain ND, Volin MV, Mandelin AM 2nd, Agrawal H. 185.  et al. 2011. Local expression of interleukin-27 ameliorates collagen-induced arthritis. Arthritis Rheum. 63:2289–98 [Google Scholar]
  186. Paradowska-Gorycka A, Raszkiewicz B, Jurkowska M, Felis-Giemza A, Romanowska-Prochnicka K. 186.  et al. 2014. Association of single nucleotide polymorphisms in the IL27 gene with rheumatoid arthritis. Scand. J. Immunol. 80:298–305 [Google Scholar]
  187. Tanida S, Yoshitomi H, Ishikawa M, Kasahara T, Murata K. 187.  et al. 2011. IL-27-producing CD14+ cells infiltrate inflamed joints of rheumatoid arthritis and regulate inflammation and chemotactic migration. Cytokine 55:237–44 [Google Scholar]
  188. Lee BH, Carcamo WC, Chiorini JA, Peck AB, Nguyen CQ. 188.  2012. Gene therapy using IL-27 ameliorates Sjogren's syndrome-like autoimmune exocrinopathy. Arthritis Res. Ther. 14:R172 [Google Scholar]
  189. Xia L, Shen H, Zhao L, Lu J. 189.  2012. Elevated levels of interleukin-27 in patients with Sjogren's syndrome. Scand. J. Rheumatol. 41:73–74 [Google Scholar]
  190. Kido M, Takeuchi S, Sugiyama N, Esaki H, Nakashima H. 190.  et al. 2011. T cell-specific overexpression of interleukin-27 receptor α subunit (WSX-1) prevents spontaneous skin inflammation in MRL/lpr mice. Br. J. Dermatol. 164:1214–34 [Google Scholar]
  191. Sugiyama N, Nakashima H, Yoshimura T, Sadanaga A, Shimizu S. 191.  et al. 2008. Amelioration of human lupus-like phenotypes in MRL/lpr mice by overexpression of interleukin 27 receptor α (WSX-1). Ann. Rheum. Dis. 67:1461–68 [Google Scholar]
  192. Igawa T, Nakashima H, Sadanaga A, Masutani K, Miyake K. 192.  et al. 2009. Deficiency in EBV-induced gene 3 (EBI3) in MRL/lpr mice results in pathological alteration of autoimmune glomerulonephritis and sialadenitis. Mod. Rheumatol. 19:33–41 [Google Scholar]
  193. Banchereau J, Pascual V. 193.  2006. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25:383–92 [Google Scholar]
  194. Li TT, Zhang T, Chen GM, Zhu QQ, Tao JH. 194.  et al. 2010. Low level of serum interleukin 27 in patients with systemic lupus erythematosus. J. Investig. Med. 58:737–39 [Google Scholar]
  195. Wittmann M, Zeitvogel J, Wang D, Werfel T. 195.  2009. IL-27 is expressed in chronic human eczematous skin lesions and stimulates human keratinocytes. J. Allergy Clin. Immunol. 124:81–89 [Google Scholar]
  196. Wittmann M, Doble R, Bachmann M, Pfeilschifter J, Werfel T, Muhl H. 196.  2012. IL-27 regulates IL-18 binding protein in skin resident cells. PLOS ONE 7:e38751 [Google Scholar]
  197. Kanda N, Watanabe S. 197.  2008. IL-12, IL-23, and IL-27 enhance human β -defensin-2 production in human keratinocytes. Eur. J. Immunol. 38:1287–96 [Google Scholar]
  198. Shibata S, Tada Y, Asano Y, Yanaba K, Sugaya M. 198.  et al. 2012. IL-27 activates Th1-mediated responses in imiquimod-induced psoriasis-like skin lesions. J. Investig. Dermatol. 133:479–88 [Google Scholar]
  199. Shibata S, Tada Y, Kanda N, Nashiro K, Kamata M. 199.  et al. 2010. Possible roles of IL-27 in the pathogenesis of psoriasis. J. Investig. Dermatol. 130:1034–39 [Google Scholar]
  200. Yoshizaki A, Yanaba K, Iwata Y, Komura K, Ogawa A. 200.  et al. 2011. Elevated serum interleukin-27 levels in patients with systemic sclerosis: association with T cell, B cell and fibroblast activation. Ann. Rheum. Dis. 70:194–200 [Google Scholar]
  201. Honda K, Nakamura K, Matsui N, Takahashi M, Kitamura Y. 201.  et al. 2005. T helper 1-inducing property of IL-27/WSX-1 signaling is required for the induction of experimental colitis. Inflamm. Bowel Dis. 11:1044–52 [Google Scholar]
  202. Sasaoka T, Ito M, Yamashita J, Nakajima K, Tanaka I. 202.  et al. 2011. Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells. Am. J. Physiol. Gastrointest. Liver Physiol. 300:G568–76 [Google Scholar]
  203. Diegelmann J, Olszak T, Göke B, Blumberg RS, Brand S. 203.  2011. A novel role for interleukin-27 (IL-27) as mediator of intestinal epithelial barrier protection mediated via differential signal transducer and activator of transcription (STAT) protein signaling and induction of antibacterial and anti-inflammatory proteins. J. Biol. Chem. 287:286–98 [Google Scholar]
  204. Li CS, Zhang Q, Lee KJ, Cho SW, Lee KM. 204.  et al. 2009. Interleukin-27 polymorphisms are associated with inflammatory bowel diseases in a Korean population. J. Gastroenterol. Hepatol. 24:1692–96 [Google Scholar]
  205. Imielinski M, Baldassano RN, Griffiths A, Russell RK, Annese V. 205.  et al. 2009. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat. Genet. 41:1335–40 [Google Scholar]
  206. Dann SM, Le C, Choudhury BK, Liu H, Saldarriaga O. 206.  et al. 2014. Attenuation of intestinal inflammation in interleukin-10-deficient mice infected with Citrobacter rodentium. Infect. Immun. 82:1949–58 [Google Scholar]
  207. Hanson ML, Hixon JA, Li W, Felber BK, Anver MR. 207.  et al. 2014. Oral delivery of IL-27 recombinant bacteria attenuates immune colitis in mice. Gastroenterology 146:210–21.e13 [Google Scholar]
  208. Fujita H, Teng A, Nozawa R, Takamoto-Matsui Y, Katagiri-Matsumura H. 208.  et al. 2009. Production of both IL-27 and IFN-γ after the treatment with a ligand for invariant NK T cells is responsible for the suppression of Th2 response and allergic inflammation in a mouse experimental asthma model. J. Immunol. 183:254–60 [Google Scholar]
  209. Dokmeci E, Xu L, Robinson E, Golubets K, Bottomly K, Herrick CA. 209.  2011. EBI3 deficiency leads to diminished T helper type 1 and increased T helper type 2 mediated airway inflammation. Immunology 132:559–66 [Google Scholar]
  210. Li JJ, Wang W, Baines KJ, Bowden NA, Hansbro PM. 210.  et al. 2010. IL-27/IFN-γ induce MyD88-dependent steroid-resistant airway hyperresponsiveness by inhibiting glucocorticoid signaling in macrophages. J. Immunol. 185:4401–9 [Google Scholar]
  211. Cao J, Wong CK, Yin Y, Lam CW. 211.  2010. Activation of human bronchial epithelial cells by inflammatory cytokines IL-27 and TNF-α: implications for immunopathophysiology of airway inflammation. J. Cell. Physiol. 223:788–97 [Google Scholar]
  212. Cao J, Zhang L, Li D, Xu F, Huang S. 212.  et al. 2012. IL-27 is elevated in patients with COPD and patients with pulmonary TB and induces human bronchial epithelial cells to produce CXCL10. Chest 141:121–30 [Google Scholar]
  213. Larousserie F, Pflanz S, Coulomb-L'Hermine A, Brousse N, Kastelein R, Devergne O. 213.  2004. Expression of IL-27 in human Th1-associated granulomatous diseases. J. Pathol. 202:164–71 [Google Scholar]
  214. Chae SC, Li CS, Kim KM, Yang JY, Zhang Q. 214.  et al. 2007. Identification of polymorphisms in human interleukin-27 and their association with asthma in a Korean population. J. Hum. Genet. 52:355–61 [Google Scholar]
  215. Huang N, Liu L, Wang XZ, Liu D, Yin SY, Yang XD. 215.  2008. Association of interleukin (IL)-12 and IL-27 gene polymorphisms with chronic obstructive pulmonary disease in a Chinese population. DNA Cell Biol. 27:527–31 [Google Scholar]
  216. Shen Y, Yuan XD, Hu D, Ke X, Wang XQ. 216.  et al. 2014. Association between Interleukin-27 gene polymorphisms and susceptibility to allergic rhinitis. Hum. Immunol. 75:991–95 [Google Scholar]
  217. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T. 217.  et al. 2006. IL-23 promotes tumour incidence and growth. Nature 442:461–65 [Google Scholar]
  218. Shimizu M, Shimamura M, Owaki T, Asakawa M, Fujita K. 218.  et al. 2006. Antiangiogenic and antitumor activities of IL-27. J. Immunol. 176:7317–24 [Google Scholar]
  219. Kachroo P, Lee MH, Zhang L, Baratelli F, Lee G. 219.  et al. 2013. IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT1-dominant pathway in human non-small cell lung cancer. J. Exp. Clin. Cancer Res. 32:97 [Google Scholar]
  220. Nielsen SR, Hammer T, Gibson J, Pepper MS, Nisato RE. 220.  et al. 2013. IL-27 inhibits lymphatic endothelial cell proliferation by STAT1-regulated gene expression. Microcirculation 20:555–64 [Google Scholar]
  221. Canale S, Cocco C, Frasson C, Seganfreddo E, Di Carlo E. 221.  et al. 2011. Interleukin-27 inhibits pediatric B-acute lymphoblastic leukemia cell spreading in a preclinical model. Leukemia 25:1815–24 [Google Scholar]
  222. Natividad KD, Junankar SR, Mohd Redzwan N, Nair R, Wirasinha RC. 222.  et al. 2013. Interleukin-27 signaling promotes immunity against endogenously arising murine tumors. PLOS ONE 8:e57469 [Google Scholar]
  223. Lu D, Zhou X, Yao L, Liu C, Jin F, Wu Y. 223.  2014. Clinical implications of the interleukin 27 serum level in breast cancer. J. Investig. Med. 62:627–31 [Google Scholar]
  224. Ho MY, Leu SJ, Sun GH, Tao MH, Tang SJ, Sun KH. 224.  2009. IL-27 directly restrains lung tumorigenicity by suppressing cyclooxygenase-2-mediated activities. J. Immunol. 183:6217–26 [Google Scholar]
  225. Zorzoli A, Di Carlo E, Cocco C, Ognio E, Ribatti D. 225.  et al. 2012. Interleukin-27 inhibits the growth of pediatric acute myeloid leukemia in NOD/SCID/Il2rg-/- mice. Clin. Cancer Res. 18:1630–40 [Google Scholar]
  226. Koltsova EK, Kim G, Lloyd KM, Saris CJ, von Vietinghoff S. 226.  et al. 2012. Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice. Circ. Res. 111:1274–85 [Google Scholar]
  227. Hirase T, Hara H, Miyazaki Y, Ide N, Nishimoto-Hazuku A. 227.  et al. 2013. Interleukin 27 inhibits atherosclerosis via immunoregulation of macrophages in mice. Am. J. Physiol. Heart Circ. Physiol. 305:H420–29 [Google Scholar]
  228. Fujimoto H, Hirase T, Miyazaki Y, Hara H, Ide-Iwata N. 228.  et al. 2011. IL-27 inhibits hyperglycemia and pancreatic islet inflammation induced by streptozotocin in mice. Am. J. Pathol. 179:2327–36 [Google Scholar]
  229. Wang R, Han G, Wang J, Chen G, Xu R. 229.  et al. 2008. The pathogenic role of interleukin-27 in autoimmune diabetes. Cell. Mol. Life Sci. 65:3851–60 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error