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Cytokine Frontiers pp 353–375Cite as

Interleukin-27: Regulation of Immune Responses and Disease Development by a Pleiotropic Cytokine with Pro- and Anti-inflammatory Properties

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Abstract

Interleukin (IL)-27 is a member of the IL-6/IL-12 heterodimeric cytokine family and has pleiotropic properties, including both pro-inflammatory and anti-inflammatory functions depending on the context. IL-27 promotes early helper T (Th)1 differentiation and generation of cytotoxic T cells and IL-10-producing regulatory T cells. In addition, IL-27 inhibits differentiation of CD4+ T cells into Th1, Th2, Th9, and Th17 cells; suppresses their responses; and limits production of pro-inflammatory cytokines. Blocking the interaction between IL-27 and its receptor or genetic knockout of their subunits exacerbates inflammatory responses in infectious and autoimmune diseases, whereas IL-27 injection or forced expression induces potent antitumor activity against a variety of mouse and human tumors and suppresses the development of inflammatory, allergic, and autoimmune diseases. In this chapter, we review the molecular characterization of IL-27 and its receptor, its pro- and anti-inflammatory properties, and the therapeutic implications.

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References

  • Airoldi I, Ribatti D (2011) Regulation of angiostatic chemokines driven by IL-12 and IL-27 in human tumors. J Leukoc Biol 90:875–882

    Article  PubMed  CAS  Google Scholar 

  • Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S, Kumar D, Burns EJ, Sherr DH, Weiner HL, Kuchroo VK (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 11:854–861

    Article  PubMed  CAS  Google Scholar 

  • Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, Kuchroo VK, Oukka M, Weiner HL (2007) A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 8:1380–1389

    Article  PubMed  CAS  Google Scholar 

  • Batten M, Li J, Yi S, Kljavin NM, Danilenko DM, Lucas S, Lee J, de Sauvage FJ, Ghilardi N (2006) Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol 7:929–936

    Article  PubMed  CAS  Google Scholar 

  • Batten M, Kljavin NM, Li J, Walter MJ, de Sauvage FJ, Ghilardi N (2008) Cutting edge: IL-27 is a potent inducer of IL-10 but not FoxP3 in murine T cells. J Immunol 180:2752–2756

    PubMed  CAS  Google Scholar 

  • Batten M, Ramamoorthi N, Kljavin NM, Ma CS, Cox JH, Dengler HS, Danilenko DM, Caplazi P, Wong M, Fulcher DA, Cook MC, King C, Tangye SG, de Sauvage FJ, Ghilardi N (2010) IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells. J Exp Med 207:2895–2906

    Article  PubMed  CAS  Google Scholar 

  • Boumendjel A, Tawk L, Malefijt Rde W, Boulay V, Yssel H, Pene J (2006) IL-27 induces the production of IgG1 by human B cells. Eur Cytokine Netw 17:281–289

    PubMed  CAS  Google Scholar 

  • Brender C, Tannahill GM, Jenkins BJ, Fletcher J, Columbus R, Saris CJ, Ernst M, Nicola NA, Hilton DJ, Alexander WS, Starr R (2007) SOCS3 regulates CD8 T cell proliferation by inhibition of IL-6 and IL-27. Blood 110:2528–2536

    Article  PubMed  CAS  Google Scholar 

  • Canale S, Cocco C, Frasson C, Seganfreddo E, Di Carlo E, Ognio E, Sorrentino C, Ribatti D, Zorzoli A, Basso G, Dufour C, Airoldi I (2011) Interleukin-27 inhibits pediatric B-acute lymphoblastic leukemia cell spreading in a preclinical model. Leukemia 25:1815–1824

    Article  PubMed  CAS  Google Scholar 

  • Cao Y, Doodes PD, Glant TT, Finnegan A (2008) IL-27 induces a Th1 immune response and susceptibility to experimental arthritis. J Immunol 180:922–930

    PubMed  CAS  Google Scholar 

  • Chen Q, Ghilardi N, Wang H, Baker T, Xie MH, Gurney A, Grewal IS, de Sauvage FJ (2000) Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature (Lond) 407:916–920

    Article  CAS  Google Scholar 

  • Chiyo M, Shimozato O, Iizasa T, Fujisawa T, Tagawa M (2004) Antitumor effects produced by transduction of dendritic cells-derived heterodimeric cytokine genes in murine colon carcinoma cells. Anticancer Res 24:3763–3767

    PubMed  CAS  Google Scholar 

  • Chiyo M, Shimozato O, Yu L, Kawamura K, Iizasa T, Fujisawa T, Tagawa M (2005) Expression of IL-27 in murine carcinoma cells produces antitumor effects and induces protective immunity in inoculated host animals. Int J Cancer 115:437–442

    Article  PubMed  CAS  Google Scholar 

  • Cocco C, Giuliani N, Di Carlo E, Ognio E, Storti P, Abeltino M, Sorrentino C, Ponzoni M, Ribatti D, Airoldi I (2010) Interleukin-27 acts as multifunctional antitumor agent in multiple myeloma. Clin Cancer Res 16:4188–4197

    Article  PubMed  CAS  Google Scholar 

  • Cocco C, Di Carlo E, Zupo S, Canale S, Zorzoli A, Ribatti D, Morandi F, Ognio E, Airoldi I (2012a) Complementary IL-23 and IL-27 anti-tumor activities cause strong inhibition of human follicular and diffuse large B-cell lymphoma growth in vivo. Leukemia 26:1365–1374

    Article  PubMed  CAS  Google Scholar 

  • Cocco C, Pistoia V, Airoldi I (2012b) Anti-leukemic properties of IL-12, IL-23 and IL-27: differences and similarities in the control of pediatric B acute lymphoblastic leukemia. Crit Rev Oncol Hematol 83:310–318

    Article  PubMed  Google Scholar 

  • Cohen J (1995) IL-12 deaths: explanation and a puzzle. Science 270:908

    Article  PubMed  CAS  Google Scholar 

  • Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature (Lond) 450:566–569

    Article  CAS  Google Scholar 

  • Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, Finkelstein D, Forbes K, Workman CJ, Brown SA, Rehg JE, Jones ML, Ni HT, Artis D, Turk MJ, Vignali DA (2010) IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol 11:1093–1101

    Article  PubMed  CAS  Google Scholar 

  • Collison LW, Delgoffe GM, Guy CS, Vignali KM, Chaturvedi V, Fairweather D, Satoskar AR, Garcia KC, Hunter CA, Drake CG, Murray PJ, Vignali DA (2012) The composition and signaling of the IL-35 receptor are unconventional. Nat Immunol 13:290–299

    Article  PubMed  CAS  Google Scholar 

  • Cox JH, Kljavin NM, Ramamoorthi N, Diehl L, Batten M, Ghilardi N (2011) IL-27 promotes T cell-dependent colitis through multiple mechanisms. J Exp Med 208:115–123

    Article  PubMed  CAS  Google Scholar 

  • Crabe S, Guay-Giroux A, Tormo AJ, Duluc D, Lissilaa R, Guilhot F, Mavoungou-Bigouagou U, Lefouili F, Cognet I, Ferlin W, Elson G, Jeannin P, Gauchat JF (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 183:7692–7702

    Article  PubMed  CAS  Google Scholar 

  • Devergne O, Hummel M, Koeppen H, Le Beau MM, Nathanson EC, Kieff E, Birkenbach M (1996) A novel interleukin-12 p40-related protein induced by latent Epstein–Barr virus infection in B lymphocytes. J Virol 70:1143–1153

    PubMed  CAS  Google Scholar 

  • Devergne O, Birkenbach M, Kieff E (1997) Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. Proc Natl Acad Sci USA 94:12041–12046

    Article  PubMed  CAS  Google Scholar 

  • Dibra D, Cutrera JJ, Xia X, Birkenbach MP, Li S (2009) Expression of WSX1 in tumors sensitizes IL-27 signaling-independent natural killer cell surveillance. Cancer Res 69:5505–5513

    Article  PubMed  CAS  Google Scholar 

  • Dibra D, Cutrera J, Xia X, Li S (2011) WSX1 expression in tumors induces immune tolerance via suppression of effector immune cells. PLoS One 6:e19072

    Article  PubMed  CAS  Google Scholar 

  • Dibra D, Cutrera JJ, Li S (2012) Coordination between TLR9 signaling in macrophages and CD3 signaling in T cells induces robust expression of IL-30. J Immunol 188:3709–3715

    Article  PubMed  CAS  Google Scholar 

  • Diveu C, McGeachy MJ, Boniface K, Stumhofer JS, Sathe M, Joyce-Shaikh B, Chen Y, Tato CM, McClanahan TK, de Waal MR, Hunter CA, Cua DJ, Kastelein RA (2009) IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. J Immunol 182:5748–5756

    Article  PubMed  CAS  Google Scholar 

  • Dokmeci E, Xu L, Robinson E, Golubets K, Bottomly K, Herrick CA (2011) EBI3 deficiency leads to diminished T helper type 1 and increased T helper type 2 mediated airway inflammation. Immunology 132:559–566

    Article  PubMed  CAS  Google Scholar 

  • El-Behi M, Ciric B, Yu S, Zhang GX, Fitzgerald DC, Rostami A (2009) Differential effect of IL-27 on developing versus committed Th17 cells. J Immunol 183:4957–4967

    Article  PubMed  CAS  Google Scholar 

  • Findlay EG, Greig R, Stumhofer JS, Hafalla JC, de Souza JB, Saris CJ, Hunter CA, Riley EM, Couper KN (2010) Essential role for IL-27 receptor signaling in prevention of Th1-mediated immunopathology during malaria infection. J Immunol 185:2482–2492

    Article  PubMed  CAS  Google Scholar 

  • Fitzgerald DC, Ciric B, Touil T, Harle H, Grammatikopolou J, Sarma JD, Gran B, Zhang GX, Rostami A (2007a) Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J Immunol 179:3268–3275

    PubMed  CAS  Google Scholar 

  • Fitzgerald DC, Zhang GX, El-Behi M, Fonseca-Kelly Z, Li H, Yu S, Saris CJ, Gran B, Ciric B, Rostami A (2007b) Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol 8:1372–1379

    Article  PubMed  CAS  Google Scholar 

  • Frank AC, Zhang X, Katsounas A, Bharucha JP, Kottilil S, Imamichi T (2010) Interleukin-27, an anti-HIV-1 cytokine, inhibits replication of hepatitis C virus. J Interferon Cytokine Res 30:427–431

    Article  PubMed  CAS  Google Scholar 

  • Freitas do Rosario AP, Lamb T, Spence P, Stephens R, Lang A, Roers A, Muller W, O’Garra A, Langhorne J (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 188:1178–1190

    Google Scholar 

  • Fujita H, Teng A, Nozawa R, Takamoto-Matsui Y, Katagiri-Matsumura H, Ikezawa Z, Ishii Y (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 183:254–260

    Article  PubMed  CAS  Google Scholar 

  • Furukawa M, Takaishi H, Takito J, Yoda M, Sakai S, Hikata T, Hakozaki A, Uchikawa S, Matsumoto M, Chiba K, Kimura T, Okada Y, Matsuo K, Yoshida H, Toyama Y (2009) IL-27 abrogates receptor activator of NF-κ B ligand-mediated osteoclastogenesis of human granulocyte-macrophage colony-forming unit cells through STAT1-dependent inhibition of c-Fos. J Immunol 183:2397–2406

    Article  PubMed  CAS  Google Scholar 

  • Garbers C, Spudy B, Aparicio-Siegmund S, Waetzig GH, Sommer J, Holscher C, Rose-John S, Grotzinger J, Lorenzen I, Scheller J (2012) An interleukin-6 receptor-dependent molecular switch mediates signal transduction of the IL-27 cytokine subunit p28 (IL-30) via a gp130 receptor homodimer. J Biol Chem 288(6):4346–4354

    Article  PubMed  CAS  Google Scholar 

  • Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kuhn R, Muller W, Trinchieri G, Sher A (1996) In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-γ and TNF-α. J Immunol 157:798–805

    Google Scholar 

  • Giuliani N, Airoldi I (2011) Novel insights into the role of interleukin-27 and interleukin-23 in human malignant and normal plasma cells. Clin Cancer Res 17:6963–6970

    Article  PubMed  CAS  Google Scholar 

  • Gonin J, Larousserie F, Bastard C, Picquenot JM, Couturier J, Radford-Weiss I, Dietrich C, Brousse N, Vacher-Lavenu MC, Devergne O (2011) Epstein–Barr virus-induced gene 3 (EBI3): a novel diagnosis marker in Burkitt lymphoma and diffuse large B-cell lymphoma. PLoS One 6:e24617

    Article  PubMed  CAS  Google Scholar 

  • Greenwell-Wild T, Vazquez N, Jin W, Rangel Z, Munson PJ, Wahl SM (2009) Interleukin-27 inhibition of HIV-1 involves an intermediate induction of type I interferon. Blood 114:1864–1874

    Article  PubMed  CAS  Google Scholar 

  • Guzzo C, Hopman WM, Che Mat NF, Wobeser W, Gee K (2010) Impact of HIV infection, highly active antiretroviral therapy, and hepatitis C coinfection on serum interleukin-27. AIDS 24:1371–1374

    PubMed  CAS  Google Scholar 

  • Guzzo C, Hopman WM, Che Mat NF, Wobeser W, Gee K (2012) IL-27-induced gene expression is downregulated in HIV-infected subjects. PLoS One 7:e45706

    Article  PubMed  CAS  Google Scholar 

  • Hall AO, Beiting DP, Tato C, John B, Oldenhove G, Lombana CG, Pritchard GH, Silver JS, Bouladoux N, Stumhofer JS, Harris TH, Grainger J, Wojno ED, Wagage S, Roos DS, Scott P, Turka LA, Cherry S, Reiner SL, Cua D, Belkaid Y, Elloso MM, Hunter CA (2012a) The cytokines interleukin 27 and interferon-γ promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37:511–523

    Article  PubMed  CAS  Google Scholar 

  • Hall AO, Silver JS, Hunter CA (2012b) The immunobiology of IL-27. Adv Immunol 115:1–44

    Article  PubMed  CAS  Google Scholar 

  • Hamano S, Himeno K, Miyazaki Y, Ishii K, Yamanaka A, Takeda A, Zhang M, Hisaeda H, Mak TW, Yoshimura A, Yoshida H (2003) WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production. Immunity 19:657–667

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto SI, Suzuki T, Nagai S, Yamashita T, Toyoda N, Matsushima K (2000) Identification of genes specifically expressed in human activated and mature dendritic cells through serial analysis of gene expression. Blood 96:2206–2214

    PubMed  CAS  Google Scholar 

  • Hibbert L, Pflanz S, De Waal MR, Kastelein RA (2003) IL-27 and IFN-alpha signal via Stat1 and Stat3 and induce T-Bet and IL-12Rβ2 in naive T cells. J Interferon Cytokine Res 23:513–522

    Article  PubMed  CAS  Google Scholar 

  • Hirahara K, Ghoreschi K, Yang XP, Takahashi H, Laurence A, Vahedi G, Sciume G, Hall AO, Dupont CD, Francisco LM, Chen Q, Tanaka M, Kanno Y, Sun HW, Sharpe AH, Hunter CA, O’Shea JJ (2012) Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1. Immunity 36:1017–1030

    Article  PubMed  CAS  Google Scholar 

  • Hisada M, Kamiya S, Fujita K, Belladonna ML, Aoki T, Koyanagi Y, Mizuguchi J, Yoshimoto T (2004) Potent antitumor activity of interleukin-27. Cancer Res 64:1152–1156

    Article  PubMed  CAS  Google Scholar 

  • Ho MY, Leu SJ, Sun GH, Tao MH, Tang SJ, Sun KH (2009) IL-27 directly restrains lung tumorigenicity by suppressing cyclooxygenase-2-mediated activities. J Immunol 183:6217–6226

    Article  PubMed  CAS  Google Scholar 

  • Holscher C, Holscher A, Ruckerl D, Yoshimoto T, Yoshida H, Mak T, Saris C, Ehlers S (2005) The IL-27 receptor chain WSX-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis. J Immunol 174:3534–3544

    PubMed  Google Scholar 

  • Hu P, Hu HD, Chen M, Peng ML, Tang L, Tang KF, Matsui M, Belladonna ML, Yoshimoto T, Zhang DZ, Xiang R, Ren H (2009) Expression of interleukins-23 and 27 leads to successful gene therapy of hepatocellular carcinoma. Mol Immunol 46:1654–1662

    Article  PubMed  CAS  Google Scholar 

  • Huber M, Steinwald V, Guralnik A, Brustle A, Kleemann P, Rosenplanter C, Decker T, Lohoff M (2008) IL-27 inhibits the development of regulatory T cells via STAT3. Int Immunol 20:223–234

    Article  PubMed  CAS  Google Scholar 

  • Hunter CA, Kastelein R (2012) Interleukin-27: balancing protective and pathological immunity. Immunity 37:960–969

    Article  PubMed  CAS  Google Scholar 

  • Imamichi T, Yang J, Huang DW, Brann TW, Fullmer BA, Adelsberger JW, Lempicki RA, Baseler MW, Lane HC (2008) IL-27, a novel anti-HIV cytokine, activates multiple interferon-inducible genes in macrophages. AIDS 22:39–45

    Article  PubMed  CAS  Google Scholar 

  • Kalliolias GD, Zhao B, Triantafyllopoulou A, Park-Min KH, Ivashkiv LB (2010) Interleukin-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling. Arthritis Rheum 62:402–413

    PubMed  CAS  Google Scholar 

  • Kamiya S, Owaki T, Morishima N, Fukai F, Mizuguchi J, Yoshimoto T (2004) An indispensable role for STAT1 in IL-27-induced T-bet expression but not proliferation of naive CD4+ T cells. J Immunol 173:3871–3877

    PubMed  CAS  Google Scholar 

  • Kamiya S, Okumura M, Chiba Y, Fukawa T, Nakamura C, Nimura N, Mizuguchi J, Wada S, Yoshimoto T (2011) IL-27 suppresses RANKL expression in CD4+ T cells in part through STAT3. Immunol Lett 138:47–53

    Article  PubMed  CAS  Google Scholar 

  • Kastelein RA, Hunter CA, Cua DJ (2007) Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 25:221–242

    Article  PubMed  CAS  Google Scholar 

  • Leonard JP, Sherman ML, Fisher GL, Buchanan LJ, Larsen G, Atkins MB, Sosman JA, Dutcher JP, Vogelzang NJ, Ryan JL (1997) Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-γ production. Blood 90:2541–2548

    PubMed  CAS  Google Scholar 

  • Liu H, Rohowsky-Kochan C (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 31:459–469

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Guan X, Ma X (2007) Regulation of IL-27 p28 gene expression in macrophages through MyD88- and interferon-γ-mediated pathways. J Exp Med 204:141–152

    Article  PubMed  CAS  Google Scholar 

  • Liu L, Wang S, Shan B, Shao L, Sato A, Kawamura K, Li Q, Ma G, Tagawa M (2008) IL-27-mediated activation of natural killer cells and inflammation produced antitumour effects for human oesophageal carcinoma cells. Scand J Immunol 68:22–29

    Article  PubMed  CAS  Google Scholar 

  • Lucas S, Ghilardi N, Li J, de Sauvage FJ (2003) IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc Natl Acad Sci USA 100:15047–15052

    Article  PubMed  CAS  Google Scholar 

  • Matsui M, Moriya O, Belladonna ML, Kamiya S, Lemonnier FA, Yoshimoto T, Akatsuka T (2004) Adjuvant activities of novel cytokines, interleukin-23 (IL-23) and IL-27, for induction of hepatitis C virus-specific cytotoxic T lymphocytes in HLA-A*0201 transgenic mice. J Virol 78:9093–9104

    Article  PubMed  CAS  Google Scholar 

  • Matsui M, Kishida T, Nakano H, Yoshimoto K, Shin-Ya M, Shimada T, Nakai S, Imanishi J, Yoshimoto T, Hisa Y, Mazda O (2009) Interleukin-27 activates natural killer cells and suppresses NK-resistant head and neck squamous cell carcinoma through inducing antibody-dependent cellular cytotoxicity. Cancer Res 69:2523–2530

    Article  PubMed  CAS  Google Scholar 

  • Mayer KD, Mohrs K, Reiley W, Wittmer S, Kohlmeier JE, Pearl JE, Cooper AM, Johnson LL, Woodland DL, Mohrs M (2008) Cutting edge: T-bet and IL-27R are critical for in vivo IFN-γ production by CD8 T cells during infection. J Immunol 180:693–697

    PubMed  CAS  Google Scholar 

  • Miyazaki Y, Inoue H, Matsumura M, Matsumoto K, Nakano T, Tsuda M, Hamano S, Yoshimura A, Yoshida H (2005) Exacerbation of experimental allergic asthma by augmented Th2 responses in WSX-1-deficient mice. J Immunol 175:2401–2407

    PubMed  CAS  Google Scholar 

  • Molle C, Nguyen M, Flamand V, Renneson J, Trottein F, De Wit D, Willems F, Goldman M, Goriely S (2007) IL-27 synthesis induced by TLR ligation critically depends on IFN regulatory factor 3. J Immunol 178:7607–7615

    PubMed  CAS  Google Scholar 

  • Molle C, Goldman M, Goriely S (2010) Critical role of the IFN-stimulated gene factor 3 complex in TLR-mediated IL-27p28 gene expression revealing a two-step activation process. J Immunol 184:1784–1792

    Article  PubMed  CAS  Google Scholar 

  • Morishima N, Owaki T, Asakawa M, Kamiya S, Mizuguchi J, Yoshimoto T (2005) Augmentation of effector CD8+ T cell generation with enhanced granzyme B expression by IL-27. J Immunol 175:1686–1693

    PubMed  CAS  Google Scholar 

  • Morishima N, Mizoguchi I, Okumura M, Chiba Y, Xu M, Shimizu M, Matsui M, Mizuguchi J, Yoshimoto T (2010) A pivotal role for interleukin-27 in CD8+ T cell functions and generation of cytotoxic T lymphocytes. J Biomed Biotechnol 2010:605483

    Article  PubMed  CAS  Google Scholar 

  • Murugaiyan G, Beynon V, Pires Da Cunha A, Joller N, Weiner HL (2012) IFN-γ limits Th9-mediated autoimmune inflammation through dendritic cell modulation of IL-27. J Immunol 189:5277–5283

    Article  PubMed  CAS  Google Scholar 

  • Neufert C, Becker C, Wirtz S, Fantini MC, Weigmann B, Galle PR, Neurath MF (2007) IL-27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1. Eur J Immunol 37:1809–1816

    Article  PubMed  CAS  Google Scholar 

  • Niedbala W, Cai B, Wei X, Patakas A, Leung BP, McInnes IB, Liew FY (2008) Interleukin 27 attenuates collagen-induced arthritis. Ann Rheum Dis 67:1474–1479

    Article  PubMed  CAS  Google Scholar 

  • Nishino R, Takano A, Oshita H, Ishikawa N, Akiyama H, Ito H, Nakayama H, Miyagi Y, Tsuchiya E, Kohno N, Nakamura Y, Daigo Y (2011) Identification of Epstein–Barr virus-induced gene 3 as a novel serum and tissue biomarker and a therapeutic target for lung cancer. Clin Cancer Res 17:6272–6286

    Article  PubMed  CAS  Google Scholar 

  • Oniki S, Nagai H, Horikawa T, Furukawa J, Belladonna ML, Yoshimoto T, Hara I, Nishigori C (2006) Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma. Cancer Res 66:6395–6404

    Article  PubMed  CAS  Google Scholar 

  • Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725

    Article  PubMed  CAS  Google Scholar 

  • Owaki T, Asakawa M, Morishima N, Hata K, Fukai F, Matusi M, Mizuguchi J, Yoshimoto T (2005) A role for IL-27 in early regulation of Th1 differentiation. J Immunol 175:2191–2200

    PubMed  CAS  Google Scholar 

  • Owaki T, Asakawa M, Fukai F, Mizuguchi J, Yoshimoto T (2006a) IL-27 induces Th1 differentiation via p38 MAPK/T-bet- and intercellular adhesion molecule-1/LFA-1/ERK1/2-dependent pathways. J Immunol 177:7579–7587

    PubMed  CAS  Google Scholar 

  • Owaki T, Asakawa M, Kamiya S, Takeda K, Fukai F, Mizuguchi J, Yoshimoto T (2006b) IL-27 suppresses CD28-mediated IL-2 production through suppressor of cytokine signaling 3. J Immunol 176:2773–2780

    PubMed  CAS  Google Scholar 

  • Owaki T, Asakawa M, Morishima N, Takeda K, Fukai F, Mizuguchi J, Yoshimoto T (2008) STAT3 is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Th1 differentiation and suppression of proinflammatory cytokine production. J Immunol 180:2903–2911

    PubMed  CAS  Google Scholar 

  • Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, Qi CF, Hwu P, Shaffer DJ, Akilesh S, Roopenian DC, Morse HC 3rd, Lipsky PE, Leonard WJ (2004) Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol 173:5361–5371

    PubMed  CAS  Google Scholar 

  • Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O’Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal MR, Moore KW (2002) A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J Immunol 168:5699–5708

    PubMed  CAS  Google Scholar 

  • Perona-Wright G, Kohlmeier JE, Bassity E, Freitas TC, Mohrs K, Cookenham T, Situ H, Pearce EJ, Woodland DL, Mohrs M (2012) Persistent loss of IL-27 responsiveness in CD8+ memory T cells abrogates IL-10 expression in a recall response. Proc Natl Acad Sci USA 109:18535–18540

    Article  PubMed  CAS  Google Scholar 

  • 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 (2002) IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16:779–790

    Article  PubMed  CAS  Google Scholar 

  • Pflanz S, Hibbert L, Mattson J, Rosales R, Vaisberg E, Bazan JF, Phillips JH, McClanahan TK, de Waal Malefyt R, Kastelein RA (2004) WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J Immunol 172:2225–2231

    PubMed  CAS  Google Scholar 

  • Pickens SR, Chamberlain ND, Volin MV, Mandelin AM 2nd, Agrawal H, Matsui M, Yoshimoto T, Shahrara S (2011) Local expression of interleukin-27 ameliorates collagen-induced arthritis. Arthritis Rheum 63:2289–2298

    Article  PubMed  CAS  Google Scholar 

  • Pirhonen J, Siren J, Julkunen I, Matikainen S (2007) IFN-alpha regulates Toll-like receptor-mediated IL-27 gene expression in human macrophages. J Leukoc Biol 82:1185–1192

    Article  PubMed  CAS  Google Scholar 

  • Pot C, Jin H, Awasthi A, Liu SM, Lai CY, Madan R, Sharpe AH, Karp CL, Miaw SC, Ho IC, Kuchroo VK (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

    Article  PubMed  CAS  Google Scholar 

  • Pot C, Apetoh L, Awasthi A, Kuchroo VK (2011) Induction of regulatory Tr1 cells and inhibition of T(H)17 cells by IL-27. Semin Immunol 23:438–445

    Article  PubMed  CAS  Google Scholar 

  • Pradhan A, Lambert QT, Reuther GW (2007) Transformation of hematopoietic cells and activation of JAK2-V617F by IL-27R, a component of a heterodimeric type I cytokine receptor. Proc Natl Acad Sci USA 104:18502–18507

    Article  PubMed  CAS  Google Scholar 

  • Rosas LE, Satoskar AA, Roth KM, Keiser TL, Barbi J, Hunter C, de Sauvage FJ, Satoskar AR (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 168:158–169

    Article  PubMed  CAS  Google Scholar 

  • Rousseau F, Basset L, Froger J, Dinguirard N, Chevalier S, Gascan H (2010) IL-27 structural analysis demonstrates similarities with ciliary neurotrophic factor (CNTF) and leads to the identification of antagonistic variants. Proc Natl Acad Sci USA 107:19420–19425

    Article  PubMed  CAS  Google Scholar 

  • Salcedo R, Stauffer JK, Lincoln E, Back TC, Hixon JA, Hahn C, Shafer-Weaver K, Malyguine A, Kastelein R, Wigginton JM (2004) IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors: role for CD8+ T cells. J Immunol 173:7170–7182

    PubMed  CAS  Google Scholar 

  • Salcedo R, Hixon JA, Stauffer JK, Jalah R, Brooks AD, Khan T, Dai RM, Scheetz L, Lincoln E, Back TC, Powell D, Hurwitz AA, Sayers TJ, Kastelein R, Pavlakis GN, Felber BK, Trinchieri G, Wigginton JM (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 182:4328–4338

    Article  PubMed  CAS  Google Scholar 

  • Schneider R, Yaneva T, Beauseigle D, El-Khoury L, Arbour N (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

    Article  PubMed  CAS  Google Scholar 

  • Seita J, Asakawa M, Ooehara J, Takayanagi S, Morita Y, Watanabe N, Fujita K, Kudo M, Mizuguchi J, Ema H, Nakauchi H, Yoshimoto T (2008) Interleukin-27 directly induces differentiation in hematopoietic stem cells. Blood 111:1903–1912

    Article  PubMed  CAS  Google Scholar 

  • Shimizu M, Shimamura M, Owaki T, Asakawa M, Fujita K, Kudo M, Iwakura Y, Takeda Y, Luster AD, Mizuguchi J, Yoshimoto T (2006) Antiangiogenic and antitumor activities of IL-27. J Immunol 176:7317–7324

    PubMed  CAS  Google Scholar 

  • Shimozato O, Sato A, Kawamura K, Chiyo M, Ma G, Li Q, Tagawa M (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–e825

    Article  PubMed  Google Scholar 

  • Shinozaki Y, Wang S, Miyazaki Y, Miyazaki K, Yamada H, Yoshikai Y, Hara H, Yoshida H (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 124:1372–1378

    Article  PubMed  CAS  Google Scholar 

  • Smits HH, van Beelen AJ, Hessle C, Westland R, de Jong E, Soeteman E, Wold A, Wierenga EA, Kapsenberg ML (2004) Commensal gram-negative bacteria prime human dendritic cells for enhanced IL-23 and IL-27 expression and enhanced Th1 development. Eur J Immunol 34:1371–1380

    Article  PubMed  CAS  Google Scholar 

  • Sprecher CA, Grant FJ, Baumgartner JW, Presnell SR, Schrader SK, Yamagiwa T, Whitmore TE, O’Hara PJ, Foster DF (1998) Cloning and characterization of a novel class I cytokine receptor. Biochem Biophys Res Commun 246:82–90

    Article  PubMed  CAS  Google Scholar 

  • 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 (2006) Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 7:937–945

    Article  PubMed  CAS  Google Scholar 

  • Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, Ernst M, Saris CJ, O’Shea JJ, Hunter CA (2007) Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol 8:1363–1371

    Article  PubMed  CAS  Google Scholar 

  • Stumhofer JS, Tait ED, Quinn WJ 3rd, Hosken N, Spudy B, Goenka R, Fielding CA, O’Hara AC, Chen Y, Jones ML, Saris CJ, Rose-John S, Cua DJ, Jones SA, Elloso MM, Grotzinger J, Cancro MP, Levin SD, Hunter CA (2010) A role for IL-27p28 as an antagonist of gp130-mediated signaling. Nat Immunol 11:1119–1126

    Article  PubMed  CAS  Google Scholar 

  • Sun J, Dodd H, Moser EK, Sharma R, Braciale TJ (2011) CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs. Nat Immunol 12:327–334

    Article  PubMed  CAS  Google Scholar 

  • Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819

    Article  PubMed  CAS  Google Scholar 

  • Takeda A, Hamano S, Yamanaka A, Hanada T, Ishibashi T, Mak TW, Yoshimura A, Yoshida H (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 170:4886–4890

    PubMed  CAS  Google Scholar 

  • Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146

    Article  PubMed  CAS  Google Scholar 

  • Villarino A, Hibbert L, Lieberman L, Wilson E, Mak T, Yoshida H, Kastelein RA, Saris C, Hunter CA (2003) The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity 19:645–655

    Article  PubMed  CAS  Google Scholar 

  • Villarino AV, Huang E, Hunter CA (2004) Understanding the pro- and anti-inflammatory properties of IL-27. J Immunol 173:715–720

    PubMed  CAS  Google Scholar 

  • Villarino AV, Larkin J 3rd, Saris CJ, Caton AJ, Lucas S, Wong T, de Sauvage FJ, Hunter CA (2005) Positive and negative regulation of the IL-27 receptor during lymphoid cell activation. J Immunol 174:7684–7691

    PubMed  CAS  Google Scholar 

  • Wang RX, Yu CR, Mahdi RM, Egwuagu CE (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 287:36012–36021

    Article  PubMed  CAS  Google Scholar 

  • Wirtz S, Becker C, Fantini MC, Nieuwenhuis EE, Tubbe I, Galle PR, Schild HJ, Birkenbach M, Blumberg RS, Neurath MF (2005) EBV-induced gene 3 transcription is induced by TLR signaling in primary dendritic cells via NF-κ B activation. J Immunol 174:2814–2824

    PubMed  CAS  Google Scholar 

  • Wirtz S, Tubbe I, Galle PR, Schild HJ, Birkenbach M, Blumberg RS, Neurath MF (2006) Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27. J Exp Med 203:1875–1881

    Article  PubMed  CAS  Google Scholar 

  • Wojno ED, Hosken N, Stumhofer JS, O’Hara AC, Mauldin E, Fang Q, Turka LA, Levin SD, Hunter CA (2011) A role for IL-27 in limiting T regulatory cell populations. J Immunol 187:266–273

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Yang Y, Qiu G, Lal G, Wu Z, Levy DE, Ochando JC, Bromberg JS, Ding Y (2009) c-Maf regulates IL-10 expression during Th17 polarization. J Immunol 182:6226–6236

    Article  PubMed  CAS  Google Scholar 

  • Xu M, Mizoguchi I, Morishima N, Chiba Y, Mizuguchi J, Yoshimoto T (2010) Regulation of antitumor immune responses by the IL-12 family cytokines, IL-12, IL-23, and IL-27. Clin Dev Immunol 2010:pii: 832454

    Google Scholar 

  • Yang J, Yang M, Htut TM, Ouyang X, Hanidu A, Li X, Sellati R, Jiang H, Zhang S, Li H, Zhao J, Ting AT, Mayer L, Unkeless JC, Labadia ME, Hodge M, Li J, Xiong H (2008) Epstein–Barr virus-induced gene 3 negatively regulates IL-17, IL-22 and RORγ t. Eur J Immunol 38:1204–1214

    Article  PubMed  CAS  Google Scholar 

  • Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363

    Article  PubMed  CAS  Google Scholar 

  • Yoshida H, Hamano S, Senaldi G, Covey T, Faggioni R, Mu S, Xia M, Wakeham AC, Nishina H, Potter J, Saris CJ, Mak TW (2001) WSX-1 is required for the initiation of Th1 responses and resistance to L. major infection. Immunity 15:569–578

    Article  PubMed  CAS  Google Scholar 

  • Yoshida H, Miyazaki Y (2008) Regulation of immune responses by interleukin-27. Immunol Rev 226:234–247

    Article  PubMed  CAS  Google Scholar 

  • Yoshimoto T, Okada K, Morishima N, Kamiya S, Owaki T, Asakawa M, Iwakura Y, Fukai F, Mizuguchi J (2004) Induction of IgG2a class switching in B cells by IL-27. J Immunol 173:2479–2485

    PubMed  CAS  Google Scholar 

  • Yoshimoto T, Yoshimoto T, Yasuda K, Mizuguchi J, Nakanishi K (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 179:4415–4423

    PubMed  CAS  Google Scholar 

  • Yoshimoto T, Morishima N, Mizoguchi I, Shimizu M, Nagai H, Oniki S, Oka M, Nishigori C, Mizuguchi J (2008) Antiproliferative activity of IL-27 on melanoma. J Immunol 180:6527–6535

    PubMed  CAS  Google Scholar 

  • Yoshimura T, Takeda A, Hamano S, Miyazaki Y, Kinjyo I, Ishibashi T, Yoshimura A, Yoshida H (2006) 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 177:5377–5385

    PubMed  CAS  Google Scholar 

  • Young A, Linehan E, Hams E, O’Hara Hall AC, McClurg A, Johnston JA, Hunter CA, Fallon PG, Fitzgerald DC (2012) Cutting edge: suppression of GM-CSF expression in murine and human T cells by IL-27. J Immunol 189:2079–2083

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Qian X, Ning H, Yang J, Xiong H, Liu J (2010) Activation of IL-27 p28 gene transcription by interferon regulatory factor 8 in cooperation with interferon regulatory factor 1. J Biol Chem 285:21269–21281

    Article  PubMed  CAS  Google Scholar 

  • Zorzoli A, Di Carlo E, Cocco C, Ognio E, Ribatti D, Ferretti E, Dufour C, Locatelli F, Montagna D, Airoldi I (2012) Interleukin-27 inhibits the growth of pediatric acute myeloid leukemia in NOD/SCID/Il2rγ−/− mice. Clin Cancer Res 18:1630–1640

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan

    Izuru Mizoguchi, Kaname Higuchi, Kana Mitobe, Ren Tsunoda & Takayuki Yoshimoto

  2. Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan

    Kaname Higuchi & Junichiro Mizuguchi

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  1. Izuru Mizoguchi
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  2. Kaname Higuchi
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  3. Kana Mitobe
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  4. Ren Tsunoda
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  5. Junichiro Mizuguchi
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  6. Takayuki Yoshimoto
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Correspondence to Takayuki Yoshimoto .

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  1. Department of Immunoregulation Institute of Medical Science, Tokyo Medical University, Tokyo, Tokyo, Japan

    Takayuki Yoshimoto

  2. Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

    Tomohiro Yoshimoto

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Mizoguchi, I., Higuchi, K., Mitobe, K., Tsunoda, R., Mizuguchi, J., Yoshimoto, T. (2014). Interleukin-27: Regulation of Immune Responses and Disease Development by a Pleiotropic Cytokine with Pro- and Anti-inflammatory Properties. In: Yoshimoto, T., Yoshimoto, T. (eds) Cytokine Frontiers. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54442-5_14

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