New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions

Nature Reviews Immunology

Volumn 5, Issue 7, 2005, Pages 521-531

  Hunter, Christopher A ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 12; INTERLEUKIN 23; INTERLEUKIN 27;

AUTOIMMUNE DISEASE; AUTOIMMUNITY; HUMAN; IMMUNE RESPONSE; INFECTION; INFLAMMATION; LYMPHOCYTE PROLIFERATION; NONHUMAN; ONTOGENY; PHENOTYPE; PRIORITY JOURNAL; REVIEW; STRUCTURE ANALYSIS; TH1 CELL; TH2 CELL;

ANIMALS; CYTOKINES; HUMANS; INFLAMMATION; INTERLEUKIN-12; INTERLEUKIN-23; INTERLEUKIN-23 SUBUNIT P19; INTERLEUKINS; MICE; MICE, KNOCKOUT; TH1 CELLS;

EID: 21844444831     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri1648     Document Type: Review

References (131)

1. 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).
2. H2 cells: a historical perspective. Nature Rev. Immunol. 2, 55-60 (2002).
3. 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).
4. + T cells through IL-12 produced by Listeria induced macrophages. Science 260, 547-549 (1993).
5. H cells. J. Exp. Med. 177, 1199-1204 (1993).
6. 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).
7. 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).
8. + 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).
9. Caspi, R. R. IL-12 in autoimmunity. Clin. Immunol. Immunopathol. 88, 4-13 (1998).
10. H1 development. Immunity 16, 755-758 (2002).
11. 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).
12. Murphy, K. M. & Reiner, S. L. The lineage decisions of helper T cells. Nature Rev. Immunol. 2, 933-944 (2002).
13. 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).
14. Heinrich, P. C. et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 374, 1-20 (2003).
15. 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).
16. 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.
17. 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).
18. Sprecher, C. A. et al. Cloning and characterization of a novel class I cytokine receptor. Biochem. Biophys. Res. Commun. 246, 82-90 (1998).
19. 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).
20. + 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.
21. Pflanz, S. et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immunol. 172, 2225-2231 (2004).
22. 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).
23. 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).
24. 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).
25. Dillon, S. R. et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nature Immunol. 5, 752-760 (2004).
26. 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).
27. H1 development. Eur. J. Immunol. 34, 1371-1380 (2004).
28. 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).
29. 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).
30. 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).
31. 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).
32. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Rev. Immunol. 3, 133-146 (2003).
33. 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).
34. 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).
35. 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).
36. 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).
37. de Jong, R. et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 280, 1435-1438 (1998).
38. Altare, F. et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280, 1432-1435 (1998).
39. 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).
40. H1-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.
41. H1 responses and resistance to L. major infection. Immunity 15, 569-578 (2001).
42. McIntyre, K. W. et al. Reduced incidence and severity of collagen-induced arthritis in interleukin-12-deficient mice. Eur. J. Immunol. 26, 2933-2938 (1997).
43. 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).
44. 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).
45. 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).
46. 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).
47. 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).
48. 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).
49. Vermeire, K. et al. Accelerated collagen-induced arthritis in IFN-γ receptor-deficient mice. J. Immunol. 158, 5507-5513 (1997).
50. 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).
51. 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).
52. 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).
53. 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.
54. 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.
55. 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.
56. 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).
57. 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).
58. 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).
59. Ghilardi, N. et al. Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice. J. Immunol. 172, 2827-2833 (2004).
60. Langrish, C. L. et al. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol. Rev. 202, 96-105 (2004).
61. Taylor, G. A., Feng, C. G. & Sher, A. p47 GTPases: regulators of immunity to intracellular pathogens. Nature Rev. Immunol. 4, 100-109 (2004).
62. H2 cell response. Eur. J. Immunol. 26, 1553-1559 (1996).
63. H1 response during Leishmania major infection. J. Immunol. 165, 896-902 (2000).
64. 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).
65. H1 response in mice infected with Cryptococcus neoformans. Infect. Immun. 66, 4994-5000 (1998).
66. 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).
67. Holscher, C. et al. A protective and agonistic function of IL-12p40 in mycobacterial infection. J. Immunol. 167, 6957-6966 (2001).
68. 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).
69. 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).
70. 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.
71. 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).
72. 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).
73. 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).
74. Suzuki, Y. et al. Impaired resistance to the development of toxoplasmic encephalitis in interleukin-6-deficient mice. Infect. Immun. 65, 2339-2345 (1997).
75. 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).
76. 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).
77. 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).
78. Greenberger, M. J. et al. IL-12 gene therapy protects mice in lethal Klebsiella pneumoniae. J. Immunol. 157, 3006-3012 (1996).
79. 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).
80. Tsai, W. C. et al. Nitric oxide is required for effective innate immunity against Klebsiella pneumoniae. Infect. Immun. 65, 1870-1875 (1997).
81. 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).
82. 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).
83. 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).
84. 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).
85. 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).
86. H1-cell responses.
87. 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).
88. H1-cell phenotype and shows that IL-27 can inhibit the expression of GATA3.
89. + T cells. J. Immunol. 173, 3871-3877 (2004).
90. H1 cytokine responses following Leishmania major infection. J. Immunol. 172, 4672-4675 (2004).
91. H1 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).
92. Villarino, A. V., Huang, E. & Hunter, C. A. Understanding the pro- and anti-inflammatory properties of IL-27. J. Immunol. 173, 715-720 (2004).
93. 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).
94. 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).
95. + T cells. J. Immunol. 173, 7170-7182 (2004).
96. Hisada, M. et al. Potent antitumor activity of interleukin-27. Cancer Res. 64, 1152-1156 (2004).
97. 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).
98. 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).
99. 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).
100. 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).
101. H2-cell responses during infection.
102. 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).
103. 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).
104. 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.
105. 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).
106. Pearl, J. E. et al. IL-27 signaling compromises control of bacterial growth in mycobacteria-infected mice. J. Immunol. 173, 7490-7496 (2004).
107. Villarino, A. V. et al. Positive and negative regulation of the IL-27 receptor during lymphoid cell activation. J. Immunol. 174, 7684-7691 (2005).
108. 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).
109. Paul, W. E. & Seder, R. A. Lymphocyte responses and cytokines. Cell 76, 241-251 (1994).
110. Barczyk, A., Pierzchala, W. & Sozanska, E. Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine. Respir. Med. 97, 726-733 (2003).
111. 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).
112. Fujino, S. et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65-70 (2003).
113. Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Med. 8, 500-508 (2002).
114. Schmidt, C. et al. Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interteukin-27p28 in Crohn's disease but not in ulcerative colitis. Inflamm. Bowel Dis. 11, 16-23 (2005).
115. 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).
116. 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).
117. 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.
118. 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).
119. H1- associated granulomatous diseases. J. Pathol. 202, 164-171 (2004).
120. 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).
121. Lenardo, M. J. Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature 353, 858-861 (1991).
122. 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).
123. 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).
124. H1 differentiation by IL-6 is mediated by SOCS1. Immunity 13, 805-815 (2000).
125. 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).
126. 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).
127. 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).
128. 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).
129. 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).
130. 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).
131. Kolls, J. K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467-476 (2004).