New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions (original) (raw)

• Mosmann, T. T., Cherwinski, H., Bond, M. W., Giedlin, M. A. & Coffman, R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2353 (1986).
  CAS PubMed Google Scholar
• Liew, F. Y. TH1 and TH2 cells: a historical perspective. Nature Rev. Immunol. 2, 55–60 (2002).
  Article CAS Google Scholar
• Kobayashi, M. et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J. Exp. Med. 170, 827–845 (1989).
  Article CAS PubMed Google Scholar
• Hsieh, C. S. et al. Devlopment of TH1 CD4+ T cells through IL-12 produced by Listeria induced macrophages. Science 260, 547–549 (1993).
  Article CAS PubMed Google Scholar
• Manetti, R. et al. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (TH1)-specific immune responses and inhibits the development of IL-4-producing TH cells. J. Exp. Med. 177, 1199–1204 (1993).
  Article CAS PubMed Google Scholar
• Tripp, C. S., Wolf, S. F. & Unanue, E. R. Interleukin 12 and tumor necrosis factor α are costimulators of interferon γ production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiological antagonist. Proc. Natl Acad. Sci. USA 90, 3725–3729 (1993).
  Article CAS PubMed PubMed Central Google Scholar
• Gazzinelli, R. T., Hieny, S., Wynn, T. A., Wolf, S. & Sher, A. Interleukin 12 is required for the T-lymphocyte-independent induction of interferon γ by an intracellular parasite and induces resistance in T-cell deficient hosts. Proc. Natl Acad. Sci. USA 90, 6115–6119 (1993).
  Article CAS PubMed PubMed Central Google Scholar
• Seder, R. A., Gazzinelli, R., Sher, A. & Paul, W. E. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon γ production and diminishes interleukin 4 inhibition of such priming. Proc. Natl Acad. Sci. USA 90, 10188–10192 (1993).
  Article CAS PubMed PubMed Central Google Scholar
• Caspi, R. R. IL-12 in autoimmunity. Clin. Immunol. Immunopathol. 88, 4–13 (1998).
  Article CAS PubMed Google Scholar
• Robinson, D. S. & O'Garra, A. Further checkpoints in TH1 development. Immunity 16, 755–758 (2002).
  Article CAS PubMed Google Scholar
• Trinchieri, G., Pflanz, S. & Kastelein, R. A. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 19, 641–644 (2003).
  Article CAS PubMed Google Scholar
• Murphy, K. M. & Reiner, S. L. The lineage decisions of helper T cells. Nature Rev. Immunol. 2, 933–944 (2002).
  Article CAS Google Scholar
• Boulay, J. L., O'Shea, J. J. & Paul, W. E. Molecular phylogeny within type I cytokines and their cognate receptors. Immunity 19, 159–163 (2003).
  Article CAS PubMed Google Scholar
• Heinrich, P. C. et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 374, 1–20 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Yoshida, K. et al. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc. Natl Acad. Sci. USA 93, 407–411 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Oppmann, B. et al. 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 (2000). This paper describes a crucial series of studies that identify IL-12p40 as a shared component of IL-12 and IL-23, and it highlights some of the similarities in the properties of these cytokines.
  Article CAS PubMed Google Scholar
• Parham, C. et al. 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 (2002).
  Article CAS PubMed Google Scholar
• Sprecher, C. A. et al. Cloning and characterization of a novel class I cytokine receptor. Biochem. Biophys. Res. Commun. 246, 82–90 (1998).
  Article CAS PubMed Google Scholar
• Devergne, O. et al. A novel interleukin-12 p40-related protein induced by latent Epstein–Barr virus infection in B lymphocytes. J. Virol. 70, 1143–1153 (1996).
  CAS PubMed PubMed Central Google Scholar
• Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002). These authors describe the identification of the unique pairing of type I cytokine components that forms IL-27 and the finding that WSX1 is required for signalling.
  Article CAS PubMed Google Scholar
• Pflanz, S. et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immunol. 172, 2225–2231 (2004).
  Article CAS PubMed Google Scholar
• Devergne, O., Birkenbach, M. & Kieff, E. 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 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Fieschi, C. et al. Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor β1 deficiency: medical and immunological implications. J. Exp. Med. 197, 527–535 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Ghilardi, N. et al. A novel type I cytokine receptor is expressed on monocytes, signals proliferation, and activates STAT-3 and STAT-5. J. Biol. Chem. 277, 16831–16836 (2002).
  Article CAS PubMed Google Scholar
• Dillon, S. R. et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nature Immunol. 5, 752–760 (2004).
  Article CAS Google Scholar
• Wirtz, S. et al. EBV-induced gene 3 transcription is induced by TLR signaling in primary dendritic cells via NF-κB activation. J. Immunol. 174, 2814–2824 (2005).
  Article CAS PubMed Google Scholar
• Smits, H. H. et al. 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 (2004).
  Article CAS PubMed Google Scholar
• Schnurr, M. et al. 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, 1582–1589 (2005).
  Article CAS PubMed Google Scholar
• Wiekowski, M. T. et al. Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J. Immunol. 166, 7563–7570 (2001).
  Article CAS PubMed Google Scholar
• Kopp, T. et al. Inflammatory skin disease in K14/p40 transgenic mice: evidence for interleukin-12-like activities of p40. J. Invest. Dermatol. 117, 618–626 (2001).
  Article CAS PubMed Google Scholar
• Kopp, T. et al. IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: evidence for enhanced cutaneous immunity. J. Immunol. 170, 5438–5444 (2003).
  Article CAS PubMed Google Scholar
• Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Rev. Immunol. 3, 133–146 (2003).
  Article CAS Google Scholar
• Tripp, C. S., Gately, M. K., Hakimi, J., Ling, P. & Unanue, E. R. Neutralization of IL-12 decreases resistance to Listeria in SCID and C.B-17 mice. J. Immunol. 152, 1883–1887 (1994).
  CAS PubMed Google Scholar
• Gazzinelli, R. T. et al. Parasite-induced IL-12 stimulates early IFN-γ synthesis and resistance during acute infection with Toxoplasma gondii. J. Immunol. 153, 2533–2543 (1994).
  CAS PubMed Google Scholar
• Heinzel, F. P., Schoenhaut, D. S., Rerko, R. M., Rosser, L. E. & Gately, M. K. Recombinant interleukin 12 cures mice infected with Leishmania major. J. Exp. Med. 177, 1505–1509 (1993).
  Article CAS PubMed Google Scholar
• Sypek, J. P. et al. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J. Exp. Med. 177, 1797–1802 (1993).
  Article CAS PubMed Google Scholar
• de Jong, R. et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 280, 1435–1438 (1998).
  Article CAS PubMed Google Scholar
• Altare, F. et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280, 1432–1435 (1998).
  Article CAS PubMed Google Scholar
• Casanova, J. L. & Abel, L. The human model: a genetic dissection of immunity to infection in natural conditions. Nature Rev. Immunol. 4, 55–66 (2004).
  Article CAS Google Scholar
• Chen, Q. et al. Development of TH1-type immune responses requires the type I cytokine receptor TCCR. Nature 407, 916–920 (2000). On the basis of analysis of mice lacking the IL-27-receptor subunit WSX1, this report was the first to link the IL-27 receptor with pro-inflammatory signalling.
  Article CAS PubMed Google Scholar
• Yoshida, H. et al. WSX-1 is required for the initiation of TH1 responses and resistance to L. major infection. Immunity 15, 569–578 (2001).
  Article CAS PubMed Google Scholar
• McIntyre, K. W. et al. Reduced incidence and severity of collagen-induced arthritis in interleukin-12-deficient mice. Eur. J. Immunol. 26, 2933–2938 (1996).
  Article CAS PubMed Google Scholar
• Neurath, M. F., Fuss, I., Kelsall, B. L., Stuber, E. & Strober, W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J. Exp. Med. 182, 1281–1290 (1995).
  Article CAS PubMed Google Scholar
• Leonard, J. P., Waldburger, K. E. & Goldman, S. J. Prevention of expeimental autoimmune encephalomyelitis by antibodies against interleukin 12. J. Exp. Med. 181, 381–386 (1995).
  Article CAS PubMed Google Scholar
• Malfait, A. M. et al. Blockade of IL-12 during the induction of collagen-induced arthritis (CIA) markedly attenuates the severity of the arthritis. Clin. Exp. Immunol. 111, 377–383 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Ferber, I. A. et al. Mice with a disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 156, 5–7 (1996).
  CAS PubMed Google Scholar
• Willenborg, D. O., Fordham, S., Bernard, C. C., Cowden, W. B. & Ramshaw, I. A. IFN-γ plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J. Immunol. 157, 3223–3227 (1996).
  CAS PubMed Google Scholar
• Chu, C. Q., Wittmer, S. & Dalton, D. K. Failure to suppress the expansion of the activated CD4 T cell population in interferon γ-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis. J. Exp. Med. 192, 123–128 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Vermeire, K. et al. Accelerated collagen-induced arthritis in IFN-γ receptor-deficient mice. J. Immunol. 158, 5507–5513 (1997).
  CAS PubMed Google Scholar
• Davidson, N. J. et al. IL-12, but not IFN-γ, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. J. Immunol. 161, 3143–3149 (1998).
  CAS PubMed Google Scholar
• Becher, B., Durell, B. G. & Noelle, R. J. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J. Clin. Invest. 110, 493–497 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Gran, B. et al. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J. Immunol. 169, 7104–7110 (2002).
  Article CAS PubMed Google Scholar
• Aggarwal, S., Ghilardi, N., Xie, M. H., de Sauvage, F. J. & Gurney, A. L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–1914 (2003). Although previous studies had indicated that IL-23 and IL-12 had some properties that were distinct from each other, these authors were the first to associate IL-23 with the production of IL-17.
  Article CAS PubMed Google Scholar
• Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003). The initial study with IL-23p19-deficient mice revealed a unique role for IL-23 and not IL-12 in the development of EAE.
  Article CAS PubMed Google Scholar
• Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005). A crucial series of experiments are described that provided evidence of a unique T-cell subset that responds to IL-23 by producing IL-17 and mediates autoimmune disease.
  Article CAS PubMed PubMed Central Google Scholar
• Murphy, C. A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Nakae, S., Nambu, A., Sudo, K. & Iwakura, Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J. Immunol. 171, 6173–6177 (2003).
  Article CAS PubMed Google Scholar
• Nakae, S. et al. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc. Natl Acad. Sci. USA 100, 5986–5990 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Ghilardi, N. et al. Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice. J. Immunol. 172, 2827–2833 (2004).
  Article CAS PubMed Google Scholar
• Langrish, C. L. et al. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol. Rev. 202, 96–105 (2004).
  Article CAS PubMed Google Scholar
• Taylor, G. A., Feng, C. G. & Sher, A. p47 GTPases: regulators of immunity to intracellular pathogens. Nature Rev. Immunol. 4, 100–109 (2004).
  Article CAS Google Scholar
• Mattner, F. et al. Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized TH2 cell response. Eur. J. Immunol. 26, 1553–1559 (1996).
  Article CAS PubMed Google Scholar
• Park, A. Y., Hondowicz, B. D. & Scott, P. IL-12 is required to maintain a TH1 response during Leishmania major infection. J. Immunol. 165, 896–902 (2000).
  Article CAS PubMed Google Scholar
• Elkins, K. L., Cooper, A., Colombini, S. M., Cowley, S. C. & Kieffer, T. L. In vivo clearance of an intracellular bacterium, Francisella tularensis LVS, is dependent on the p40 subunit of interleukin-12 (IL-12) but not on IL-12 p70. Infect. Immun. 70, 1936–1948 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Decken, K. et al. Interleukin-12 is essential for a protective TH1 response in mice infected with Cryptococcus neoformans. Infect. Immun. 66, 4994–5000 (1998).
  CAS PubMed PubMed Central Google Scholar
• Lehmann, J. et al. IL-12p40-dependent agonistic effects on the development of protective innate and adaptive immunity against Salmonella enteritidis. J. Immunol. 167, 5304–5315 (2001).
  Article CAS PubMed Google Scholar
• Holscher, C. et al. A protective and agonistic function of IL-12p40 in mycobacterial infection. J. Immunol. 167, 6957–6966 (2001).
  Article CAS PubMed Google Scholar
• Carr, J. A., Rogerson, J. A., Mulqueen, M. J., Roberts, N. A. & Nash, A. A. The role of endogenous interleukin-12 in resistance to murine cytomegalovirus (MCMV) infection and a novel action for endogenous IL-12 p40. J. Interferon Cytokine Res. 19, 1145–1152 (1999).
  Article CAS PubMed Google Scholar
• Lieberman, L. A. et al. IL-23 provides a limited mechanism of resistance to acute toxoplasmosis in the absence of IL-12. J. Immunol. 173, 1887–1893 (2004).
  Article CAS PubMed Google Scholar
• Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194, 519–527 (2001). This was the first description of a role for IL-17 in the regulation of neutrophil mobilization and host resistance to infection.
  Article CAS PubMed PubMed Central Google Scholar
• Happel, K. I. et al. Roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J. Immunol. 170, 4432–4436 (2003).
  Article CAS PubMed Google Scholar
• Kelly, M. N. et al. Interleukin-17/interleukin-17 receptor-mediated signaling is important for generation of an optimal polymorphonuclear response against Toxoplasma gondii infection. Infect. Immun. 73, 617–621 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Hunter, C. A., Abrams, J. S., Beaman, M. H. & Remington, J. S. Cytokine mRNA in the central nervous system of SCID mice infected with Toxoplasma gondii: importance of T-cell-independent regulation of resistance to T. gondii. Infect. Immun. 61, 4038–4044 (1993).
  CAS PubMed PubMed Central Google Scholar
• Suzuki, Y. et al. Impaired resistance to the development of toxoplasmic encephalitis in interleukin-6-deficient mice. Infect. Immun. 65, 2339–2345 (1997).
  CAS PubMed PubMed Central Google Scholar
• Deckert-Schluter, M., Bluethmann, H., Rang, A., Hof, H. & Schluter, D. Crucial role of TNF receptor type 1 (p55), but not of TNF receptor type 2 (p75), in murine toxoplasmosis. J. Immunol. 160, 3427–3436 (1998).
  CAS PubMed Google Scholar
• Yap, G. S., Scharton-Kersten, T., Charest, H. & Sher, A. Decreased resistance of TNF receptor p55- and p75-deficient mice to chronic toxoplasmosis despite normal activation of inducible nitric oxide synthase in vivo. J. Immunol. 160, 1340–1345 (1998).
  CAS PubMed Google Scholar
• Bettelli, E. & Kuchroo, V. K. IL-12- and IL-23-induced T helper cell subsets: birds of the same feather flock together. J. Exp. Med. 201, 169–171 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Greenberger, M. J. et al. IL-12 gene therapy protects mice in lethal Klebsiella pneumoniae. J. Immunol. 157, 3006–3012 (1996).
  CAS PubMed Google Scholar
• Deng, J. C. et al. STAT4 is a critical mediator of early innate immune responses against pulmonary Klebsiella infection. J. Immunol. 173, 4075–4083 (2004).
  Article CAS PubMed Google Scholar
• Tsai, W. C. et al. Nitric oxide is required for effective innate immunity against Klebsiella pneumoniae. Infect. Immun. 65, 1870–1875 (1997).
  CAS PubMed PubMed Central Google Scholar
• Moore, T. A., Perry, M. L., Getsoian, A. G., Newstead, M. W. & Standiford, T. J. Divergent role of γ interferon in a murine model of pulmonary versus systemic Klebsiella pneumoniae infection. Infect. Immun. 70, 6310–6318 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Suzuki, Y., Orelana, M. A., Schreiber, R. D. & Remington, J. S. Inteferon-γ: the major mediator of resistance against Toxoplasma gondii. Science 240, 516–518 (1988).
  Article CAS PubMed Google Scholar
• Cai, G., Radzanowski, T., Villegas, E. N., Kastelein, R. & Hunter, C. A. Identification of STAT4-dependent and independent mechanisms of resistance to Toxoplasma gondii. J. Immunol. 165, 2619–2627 (2000).
  Article CAS PubMed Google Scholar
• Scharton-Kersten, T. M., Yap, G., Magram, J. & Sher, A. Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii. J. Exp. Med. 185, 1261–1273 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Teunissen, M. B., Koomen, C. W., de Waal Malefyt, R., Wierenga, E. A. & Bos, J. D. Interleukin-17 and interferon-γ synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J. Invest. Dermatol. 111, 645–649 (1998).
  Article CAS PubMed Google Scholar
• Takeda, A. et al. 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 (2003). This is the initial description of the signalling components that are used by IL-27 and that could promote T H 1-cell responses.
  Article CAS PubMed Google Scholar
• Hibbert, L., Pflanz, S., De Waal Malefyt, R. & Kastelein, R. A. IL-27 and IFN-α signal via Stat1 and Stat3 and induce T-Bet and IL-12Rβ2 in naive T cells. J. Interferon Cytokine Res. 23, 513–522 (2003).
  Article CAS PubMed Google Scholar
• Lucas, S., Ghilardi, N., Li, J. & de Sauvage, F. J. 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 (2003). This paper provides insights into the ability of IL-27 to enhance the polarization of CD4+ T cells to a T H 1-cell phenotype and shows that IL-27 can inhibit the expression of GATA3.
  Article CAS PubMed PubMed Central Google Scholar
• Kamiya, S. et al. 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 (2004).
  Article CAS PubMed Google Scholar
• Artis, D. et al. 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, 4672–4675 (2004).
  Article CAS PubMed Google Scholar
• Zahn, S. et al. Impaired TH1 responses in mice deficient in Epstein–Barr virus-induced gene 3 and challenged with physiological doses of Leishmania major. Eur. J. Immunol. 35, 1106–1112 (2005).
  Article CAS PubMed Google Scholar
• Villarino, A. V., Huang, E. & Hunter, C. A. Understanding the pro- and anti-inflammatory properties of IL-27. J. Immunol. 173, 715–720 (2004).
  Article CAS PubMed Google Scholar
• Chiyo, M. et al. 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 (2005).
  Article CAS PubMed Google Scholar
• Matsui, M. et al. 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 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Salcedo, R. et al. IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors: role for CD8+ T cells. J. Immunol. 173, 7170–7182 (2004).
  Article CAS PubMed Google Scholar
• Hisada, M. et al. Potent antitumor activity of interleukin-27. Cancer Res. 64, 1152–1156 (2004).
  Article CAS PubMed Google Scholar
• Larousserie, F. et al. Analysis of interleukin-27 (EBI3/p28) expression in Epstein–Barr virus- and human T-cell leukemia virus type 1-associated lymphomas: heterogeneous expression of EBI3 subunit by tumoral cells. Am. J. Pathol. 166, 1217–1228 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Goldberg, R., Wildbaum, G., Zohar, Y., Maor, G. & Karin, N. Suppression of ongoing adjuvant-induced arthritis by neutralizing the function of the p28 subunit of IL-27. J. Immunol. 173, 1171–1178 (2004).
  Article CAS PubMed Google Scholar
• Goldberg, R. et al. Suppression of ongoing experimental autoimmune encephalomyelitis by neutralizing the function of the p28 subunit of IL-27. J. Immunol. 173, 6465–6471 (2004).
  Article CAS PubMed Google Scholar
• Nieuwenhuis, E. E. et al. Disruption of T helper 2-immune responses in Epstein–Barr virus-induced gene 3-deficient mice. Proc. Natl Acad. Sci. USA 99, 16951–16956 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Hamano, S. et al. WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production. Immunity 19, 657–667 (2003). This is one of the initial studies that showed that IL-27-receptor-deficient mice develop exaggerated T H 1- and T H 2-cell responses during infection.
  Article CAS PubMed Google Scholar
• Artis, D. et al. The IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of type 2 immunity. J. Immunol. 173, 5626–5634 (2004).
  Article CAS PubMed Google Scholar
• Holscher, C. et al. The IL-27 receptor chain WSX-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis. J. Immunol. 174, 3534–3544 (2005).
  Article PubMed Google Scholar
• Villarino, A. et al. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity 19, 645–655 (2003). This was the first report to propose an anti-inflammatory function for IL-27 in the context of infection.
  Article CAS PubMed Google Scholar
• Yamanaka, A. et al. Hyperproduction of proinflammatory cytokines by WSX-1-deficient NKT cells in concanavalin A-induced hepatitis. J. Immunol. 172, 3590–3596 (2004).
  Article CAS PubMed Google Scholar
• Pearl, J. E. et al. IL-27 signaling compromises control of bacterial growth in mycobacteria-infected mice. J. Immunol. 173, 7490–7496 (2004).
  Article CAS PubMed Google Scholar
• Villarino, A. V. et al. Positive and negative regulation of the IL-27 receptor during lymphoid cell activation. J. Immunol. 174, 7684–7691 (2005).
  Article CAS PubMed Google Scholar
• Bancroft, A. J., Humphreys, N. E., Worthington, J. J., Yoshida, H. & Grencis, R. K. WSX-1: a key role in induction of chronic intestinal nematode infection. J. Immunol. 172, 7635–7641 (2004).
  Article CAS PubMed Google Scholar
• Paul, W. E. & Seder, R. A. Lymphocyte responses and cytokines. Cell 76, 241–251 (1994).
  Article CAS PubMed Google Scholar
• Barczyk, A., Pierzchala, W. & Sozanska, E. Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine. Respir. Med. 97, 726–733 (2003).
  Article CAS PubMed Google Scholar
• Casado, B., Pannell, L. K., Viglio, S., Iadarola, P. & Baraniuk, J. N. Analysis of the sinusitis nasal lavage fluid proteome using capillary liquid chromatography interfaced to electrospray ionization-quadrupole time of flight-tandem mass spectrometry. Electrophoresis 25, 1386–1393 (2004).
  Article CAS PubMed Google Scholar
• Fujino, S. et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Med. 8, 500–508 (2002).
  Article CAS PubMed Google Scholar
• Schmidt, C. et al. Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn's disease but not in ulcerative colitis. Inflamm. Bowel Dis. 11, 16–23 (2005).
  Article PubMed Google Scholar
• Lee, E. et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J. Exp. Med. 199, 125–130 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• McAllister, F. et al. Role of IL-17A, IL-17F and the IL-17 receptor in regulating Gro-α and G-CSF in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J. Immunol. (in the press).
• Mannon, P. J. et al. Anti-interleukin-12 antibody for active Crohn's disease. N. Engl. J. Med. 351, 2069–2079 (2004). This paper describes the results of the clinical trial using IL-12p40-specific antibodies, which indicate that this cytokine component is a viable clinical target.
  Article CAS PubMed Google Scholar
• Gardam, M. A. et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect. Dis. 3, 148–155 (2003).
  Article CAS PubMed Google Scholar
• Larousserie, F. et al. Expression of IL-27 in human TH1-associated granulomatous diseases. J. Pathol. 202, 164–171 (2004).
  Article CAS PubMed Google Scholar
• Omata, F., Birkenbach, M., Matsuzaki, S., Christ, A. D. & Blumberg, R. S. The expression of IL-12 p40 and its homologue, Epstein–Barr virus-induced gene 3, in inflammatory bowel disease. Inflamm. Bowel Dis. 7, 215–220 (2001).
  Article CAS PubMed Google Scholar
• Lenardo, M. J. Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature 353, 858–861 (1991).
  Article CAS PubMed Google Scholar
• Hodge-Dufour, J. et al. Inhibition of interferon γ induced interleukin 12 production: a potential mechanism for the anti-inflammatory activities of tumor necrosis factor. Proc. Natl Acad. Sci. USA 95, 13806–13811 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Cope, A. P. et al. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signalling. J. Exp. Med. 185, 1573–1584 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Diehl, S. et al. Inhibition of TH1 differentiation by IL-6 is mediated by SOCS1. Immunity 13, 805–815 (2000).
  Article CAS PubMed Google Scholar
• Cousens, L. P., Orange, J. S., Su, H. C. & Biron, C. A. Interferon-α/β inhibition of interleukin 12 and interferon-γ production in vitro during viral infection. Proc. Natl Acad. Sci. USA 94, 634–639 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, C. K., Smith, E., Gimeno, R., Gertner, R. & Levy, D. E. STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-γ. J. Immunol. 164, 1286–1292 (2000).
  Article CAS PubMed Google Scholar
• Tebbutt, N. C. et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nature Med. 8, 1089–1097 (2002).
  Article CAS PubMed Google Scholar
• Ishida, H., Hastings, R., Kearney, J. & Howard, M. Continuous anti-interleukin 10 antibody administration depletes mice of Ly-1 B cells but not conventional B cells. J. Exp. Med. 175, 1213–1220 (1992).
  Article CAS PubMed Google Scholar
• Cai, G., Kastelein, R. A. & Hunter, C. A. IL-10 enhances NK cell proliferation, cytotoxicity and production of IFN-γ when combined with IL-18. Eur. J. Immunol. 29, 2658–2665 (1999).
  Article CAS PubMed Google Scholar
• Shibata, Y. et al. Immunoregulatory roles of IL-10 in innate immunity: IL-10 inhibits macrophage production of IFN-γ-inducing factors but enhances NK cell production of IFN-γ. J. Immunol. 161, 4283–4288 (1998).
  CAS PubMed Google Scholar
• Kolls, J. K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).
  Article CAS PubMed Google Scholar