Interleukin-12 and the regulation of innate resistance and adaptive immunity (original) (raw)

• Janeway, C. A. Jr. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol. Today 13, 11–16 (1992).
  Article CAS PubMed Google Scholar
• Rock, F. L., Hardiman, G., Timans, J. C., Kastelein, R. A. & Bazan, J. F. A family of human receptors structurally related to Drosophila Toll. Proc. Natl Acad. Sci. USA 95, 588–593 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Lertmemongkolchai, G., Cai, G., Hunter, C. A. & Bancroft, G. J. Bystander activation of CD8+ T cells contributes to the rapid production of IFN-γ in response to bacterial pathogens. J. Immunol. 166, 1097–1105 (2001). This paper reports important experimental evidence in vivo in support of the concept that antigen-non-specific bystander T cells have an important role in the early production of pro-inflammatory cytokines in innate resistance.
  Article CAS PubMed Google Scholar
• Cui, J. et al. Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors. Science 278, 1623–1626 (1997).
  Article CAS PubMed Google Scholar
• Ohteki, T. et al. Interleukin-12-dependent interferon-γ production by CD8α+ lymphoid dendritic cells. J. Exp. Med. 189, 1981–1986 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Airoldi, I. et al. Expression and function of IL-12 and IL-18 receptors on human tonsillar B cells. J. Immunol. 165, 6880–6888 (2000).
  Article CAS PubMed Google Scholar
• Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).
  Article CAS PubMed Google Scholar
• Le Gros, G., Ben-Sasson, S. Z., Seder, R., Finkelman, F. D. & Paul, W. E. Generation of interleukin-4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J. Exp. Med. 172, 921–929 (1990).
  Article CAS PubMed 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, 827–846 (1989). This paper reports the first identification of IL-12, its functions and its heterodimeric structure.
  Article CAS PubMed Google Scholar
• Hsieh, C. S. et al. Development of TH1 CD4+ T cells through IL-12 produced by _Listeria_-induced macrophages. Science 260, 547–549 (1993). This study was the first to show the pivotal role of IL-12 in T H 1-cell differentiation in the mouse.
  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). This study was the first demonstration of the ability of IL-12 to induce the differentiation of T H 1-cell clones.
  Article CAS PubMed Google Scholar
• Stern, A. S. et al. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc. Natl Acad. Sci. USA 87, 6808–6812 (1990).
  Article CAS PubMed PubMed Central Google Scholar
• D'Andrea, A. et al. Production of natural killer cell stimulatory factor (interleukin-12) by peripheral-blood mononuclear cells. J. Exp. Med. 176, 1387–1398 (1992).
  Article CAS PubMed Google Scholar
• Macatonia, S. E. et al. Dendritic cells produce IL-12 and direct the development of TH1 cells from naive CD4+ T cells. J. Immunol. 154, 5071–5079 (1995). This paper describes how dendritic cells (DCs) induce T H 1-cell differentiation by producing IL-12 in response to antigen-activated T cells.
  CAS PubMed Google Scholar
• Merberg, D. M., Wolf, S. F. & Clark, S. C. Sequence similarity between NKSF and the IL-6/G-CSF family. Immunol. Today 13, 77–78 (1992).
  Article CAS PubMed 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 study reports the identification of IL-23.
  Article CAS PubMed Google Scholar
• Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and novel p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002). This study reports the identification of IL-27.
  Article CAS PubMed Google Scholar
• Presky, D. H. et al. A functional interleukin-12 receptor complex is composed of two β-type cytokine receptor subunits. Proc. Natl Acad. Sci. USA 93, 14002–14007 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Thierfelder, W. E. et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382, 171–174 (1996).
  Article CAS PubMed Google Scholar
• Kaplan, M. H., Sun, Y. L., Hoey, T. & Grusby, M. J. Impaired IL-12 responses and enhanced development of TH2 cells in Stat4-deficient mice. Nature 382, 174–177 (1996).
  Article CAS PubMed Google Scholar
• Grohmann, U. et al. IL-12 acts directly on DC to promote nuclear localization of NF-κB and primes DC for IL-12 production. Immunity 9, 315–323 (1998).
  Article CAS PubMed Google Scholar
• Rogge, L. et al. Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J. Exp. Med. 185, 825–831 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Szabo, S. J., Dighe, A. S., Gubler, U. & Murphy, K. M. Regulation of the interleukin (IL)-12R β2-subunit expression in developing T helper 1 (TH1) and TH2 cells. J. Exp. Med. 185, 817–824 (1997). References 22 and 23 show, in humans and in mice, that unresponsiveness of T H 2 cells to IL-12 is owing to down-regulation of expression of IL-12Rβ2.
  Article CAS PubMed PubMed Central Google Scholar
• Wysocka, M. et al. Interleukin-12 is required for interferon-γ production and lethality in lipopolysaccharide-induced shock in mice. Eur. J. Immunol. 25, 672–676 (1995).
  Article CAS PubMed Google Scholar
• Carra, G., Gerosa, F. & Trinchieri, G. Biosynthesis and posttranslational regulation of human IL-12. J. Immunol. 164, 4752–4761 (2000).
  Article CAS PubMed Google Scholar
• Gillessen, S. et al. Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist. Eur. J. Immunol. 25, 200–206 (1995).
  Article CAS PubMed Google Scholar
• Heinzel, F. P., Hujer, A. M., Ahmed, F. N. & Rerko, R. M. In vivo production and function of IL-12 p40 homodimers. J. Immunol. 158, 4381–4388 (1997).
  CAS PubMed Google Scholar
• Sousa, C. R. et al. In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin-12 by dendritic cells and their redistribution to T-cell areas. J. Exp. Med. 186, 1819–1829 (1997).
  Article PubMed Central 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). This study describes the central role of IL-12 in resistance to intracellular parasites, both in wild-type and SCID mice, and shows the participation of this cytokine in the mechanism of T-cell-independent macrophage activation.
  CAS PubMed Google Scholar
• Scharton-Kersten, T. M. et al. In the absence of endogenous IFN-γ, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. J. Immunol. 157, 4045–4054 (1996).
  CAS PubMed Google Scholar
• Schulz, O. et al. CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity 13, 453–462 (2000).
  Article CAS PubMed Google Scholar
• Dalod, M. et al. Interferon-α/β and interleukin-12 responses to viral infections: pathways regulating dendritic-cell cytokine expression in vivo. J. Exp. Med. 195, 517–528 (2002). This study reports that in response to virus infection in vivo, mouse type-I IFN-producing cells synthesize both IFN-α and IL-12, and that different subsets of DC produce IL-12 in response to bacterial and viral infections.
  Article CAS PubMed PubMed Central Google Scholar
• Ma, X., Neurath, M., Gri, G. & Trinchieri, G. Identification and characterization of a novel Ets-2-related nuclear complex implicated in the activation of the human interleukin-12 p40 gene promoter. J. Biol. Chem. 272, 10389–10395 (1997).
  Article CAS PubMed Google Scholar
• Aliberti, J. et al. CCR5 provides a signal for microbial-induced production of IL-12 by CD8α+ dendritic cells. Nature Immunol. 1, 83–87 (2000).
  Article CAS Google Scholar
• Grumont, R. et al. c-Rel regulates interleukin-12 p70 expression in CD8+ dendritic cells by specifically inducing p35 gene transcription. J. Exp. Med. 194, 1021–1032 (2001). This paper identifies a differential requirement for c-REL for transcription of the genes encoding IL-12 p35 and p40 in DCs and macrophages, respectively.
  Article CAS PubMed PubMed Central Google Scholar
• Wolf, S. F. et al. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J. Immunol. 146, 3074–3081 (1991). This study reports the cloning of the genes encoding the two chains of IL-12.
  CAS PubMed Google Scholar
• Ma, X. & Trinchieri, G. Regulation of interleukin-12 production in antigen-presenting cells. Adv. Immunol. 79, 55–92 (2001).
  Article CAS PubMed Google Scholar
• Snijders, A. et al. Regulation of bioactive IL-12 production in lipopolysaccharide-stimulated human monocytes is determined by the expression of the p35 subunit. J. Immunol. 156, 1207–1212 (1996).
  CAS PubMed Google Scholar
• Jarrossay, D., Napolitani, G., Colonna, M., Sallusto, F. & Lanzavecchia, A. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur. J. Immunol. 31, 3388–3393 (2001).
  Article CAS PubMed Google Scholar
• Kadowaki, N. et al. Subsets of human dendritic-cell precursors express different Toll-like receptors and respond to different microbial antigens. J. Exp. Med. 194, 863–869 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Hayes, M. P., Murphy, F. J. & Burd, P. R. Interferon-γ-dependent inducible expression of the human interleukin-12 p35 gene in monocytes initiates from a TATA-containing promoter distinct from the CpG-rich promoter active in Epstein–Barr virus-transformed lymphoblastoid cells. Blood 91, 4645–4651 (1998).
  CAS PubMed Google Scholar
• Ma, X. et al. The interleukin-12 p40 gene promoter is primed by interferon-γ in monocytic cells. J. Exp. Med. 183, 147–157 (1996).
  Article CAS PubMed Google Scholar
• D'Andrea, A., Ma, X., Aste-Amezaga, M., Paganin, C. & Trinchieri, G. Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral-blood mononuclear cells: priming for IL-12 and tumor-necrosis factor-α production. J. Exp. Med. 181, 537–546 (1995).
  Article CAS PubMed Google Scholar
• Marshall, J. D., Robertson, S. E., Trinchieri, G. & Chehimi, J. Priming with IL-4 and IL-13 during HIV-1 infection restores in vitro IL-12 production by mononuclear cells of HIV-infected patients. J. Immunol. 159, 5705–5714 (1997).
  CAS PubMed Google Scholar
• Cella, M. et al. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T-cell stimulatory capacity: T–T help via APC activation. J. Exp. Med. 184, 747–752 (1996).
  Article CAS PubMed Google Scholar
• Kalinski, P. et al. IL-4 is a mediator of IL-12p70 induction by human TH2 cells: reversal of polarized TH2 phenotype by dendritic cells. J. Immunol. 165, 1877–1881 (2000).
  Article CAS PubMed Google Scholar
• Kato, T., Hakamada, R., Yamane, H. & Nariuchi, H. Induction of IL-12 p40 messenger RNA expression and IL-12 production of macrophages via CD40–CD40 ligand interaction. J. Immunol. 156, 3932–3938 (1996).
  CAS PubMed Google Scholar
• Vaidyanathan, H., Gentry, J. D., Weatherman, A., Schwartzbach, S. D. & Petro, T. M. Differential response of the murine IL-12 p35 gene to lipopolysaccharide compared with interferon-γ and CD40 ligation. Cytokine 16, 1–9 (2001).
  Article CAS PubMed Google Scholar
• Gerosa, F. et al. Reciprocal activating interaction between natural killer cells and dendritic cells. J. Exp. Med. 195, 327–333 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Aste-Amezaga, M., Ma, X., Sartori, A. & Trinchieri, G. Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J. Immunol. 160, 5936–5944 (1998).
  CAS PubMed Google Scholar
• D'Andrea, A. et al. Interleukin-10 inhibits human lymphocyte IFN-γ production by suppressing natural killer cell stimulatory factor/interleukin-12 synthesis in accessory cells. J. Exp. Med. 178, 1041–1048 (1993).
  Article CAS PubMed Google Scholar
• Jankovic, D. et al. In the absence of IL-12, CD4+ T-cell responses to intracellular pathogens fail to default to a TH2 pattern and are host protective in an IL-10(−/−) setting. Immunity 16, 429–439 (2002). This study shows that during an infection, T H 1 cells that produce low levels of IFN-γ can be generated in the absence of IL-12, but not in the absence of signalling through Toll-like receptors. The T H 1 cells that are generated in the absence of IL-12 cannot protect the animals unless the animals are also deficient for IL-10.
  Article CAS PubMed Google Scholar
• Gazzinelli, R. T. et al. 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 (1996).
  CAS PubMed Google Scholar
• Belkaid, Y. et al. The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J. Exp. Med. 194, 1497–1506 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Du, C. & Sriram, S. Mechanism of inhibition of LPS-induced IL-12p40 production by IL-10 and TGF-β in ANA-1 cells. J. Leukocyte Biol. 64, 92–97 (1998).
  Article CAS PubMed Google Scholar
• Cousens, L. P. et al. Two roads diverged: interferon α/β- and interleukin-12-mediated pathways in promoting T-cell interferon-γ responses during viral infection. J. Exp. Med. 189, 1315–1328 (1999). This study indicates the roles of both IL-12 and IFN-α in IFN-γ production in the mouse, and the cross-regulation of these two cytokines.
  Article CAS PubMed PubMed Central Google Scholar
• Braun, M. C. & Kelsall, B. L. Regulation of interleukin-12 production by G-protein-coupled receptors. Microbes Infect. 3, 99–107 (2001).
  Article CAS PubMed Google Scholar
• van der Pouw Kraan, T. C., Boeije, L. C., Smeenk, R. J., Wijdenes, J. & Aarden, L. A. Prostaglandin-E2 is a potent inhibitor of human interleukin-12 production. J. Exp. Med. 181, 775–779 (1995).
  Article CAS PubMed Google Scholar
• Weinmann, A. S. et al. Nucleosome remodeling at the IL-12 p40 promoter is a TLR-dependent, Rel-independent event. Nature Immunol. 2, 51–57 (2001).
  Article CAS Google Scholar
• Hayes, M. P., Wang, J. & Norcross, M. A. Regulation of interleukin-12 expression in human monocytes: selective priming by interferon-γ of lipopolysaccharide-inducible p35 and p40 genes. Blood 86, 646–650 (1995).
  CAS PubMed Google Scholar
• Tone, Y. et al. Structure and chromosomal location of the mouse interleukin-12 p35 and p40 subunit genes. Eur. J. Immunol. 26, 1222–1227 (1996).
  Article CAS PubMed Google Scholar
• Yoshimoto, T. et al. Molecular cloning and characterization of murine IL-12 genes. J. Immunol. 156, 1082–1088 (1996).
  CAS PubMed Google Scholar
• Babik, J. M. et al. Expression of murine IL-12 is regulated by translational control of the p35 subunit. J. Immunol. 162, 4069–4078 (1999).
  CAS PubMed Google Scholar
• Murphy, F. J., Hayes, M. P. & Burd, P. R. Disparate intracellular processing of human IL-12 preprotein subunits: atypical processing of the P35 signal peptide. J. Immunol. 164, 839–847 (2000).
  Article CAS PubMed Google Scholar
• Trinchieri, G. Interleukin-12: a cytokine at the interface of inflammation and immunity. Adv. Immunol. 70, 83–243 (1998).
  Article CAS PubMed Google Scholar
• Piccotti, J. R. et al. Alloantigen-reactive TH1 development in IL-12-deficient mice. J. Immunol. 160, 1132–1138 (1998).
  CAS PubMed Google Scholar
• Cooper, A. M. et al. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J. Immunol. 168, 1322–1327 (2002).
  Article 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
• Perussia, B. et al. Natural killer (NK)-cell stimulatory factor or IL-12 has differential effects on the proliferation of TCR-αβ+, TCR-γδ+ T lymphocytes, and NK cells. J. Immunol. 149, 3495–3502 (1992).
  CAS PubMed Google Scholar
• Kubin, M., Kamoun, M. & Trinchieri, G. Interleukin-12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. J. Exp. Med. 180, 211–222 (1994).
  Article CAS PubMed Google Scholar
• Murphy, E. E. et al. B7 and interleukin-12 cooperate for proliferation and interferon-γ production by mouse T helper clones that are unresponsive to B7 costimulation. J. Exp. Med. 180, 223–231 (1994). References 70 and 71 show that in both humans and mice, IL-12 is strongly synergistic with co-stimulatory signals (such as B7–CD28 interactions) for inducing IFN-γ production by and proliferation of both resting and activated T cells, even in the absence of antigen.
  Article CAS PubMed Google Scholar
• Chan, S. H. et al. Induction of IFN-γ production by NK-cell stimulatory factor (NKSF): characterization of the responder cells and synergy with other inducers. J. Exp. Med. 173, 869–879 (1991).
  Article CAS PubMed Google Scholar
• Hunter, C. A., Chizzonite, R. & Remington, J. S. IL-1β is required for IL-12 to induce production of IFN-γ by NK cells. A role for IL-1β in the T-cell-independent mechanism of resistance against intracellular pathogens. J. Immunol. 155, 4347–4354 (1995).
  CAS PubMed Google Scholar
• Chan, S. H., Kobayashi, M., Santoli, D., Perussia, B. & Trinchieri, G. Mechanisms of IFN-γ induction by natural killer cell stimulatory factor (NKSF/IL-12): role of transcription and mRNA stability in the synergistic interaction between NKSF and IL-2. J. Immunol. 148, 92–98 (1992).
  CAS PubMed Google Scholar
• Walker, W., Aste-Amezaga, M., Kastelein, R. A., Trinchieri, G. & Hunter, C. A. IL-18 and CD28 use distinct molecular mechanisms to enhance NK-cell production of IL-12-induced IFN-γ. J. Immunol. 162, 5894–5901 (1999).
  CAS PubMed Google Scholar
• Hodge, D. L., Martinez, A., Julias, J. G., Taylor, L. S. & Young, H. A. Regulation of nuclear γ-interferon gene expression by interleukin-12 (IL-12) and IL-2 represents a novel form of posttranscriptional control. Mol. Cell. Biol. 22, 1742–1753 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Okamura, H., Tsutsui, H., Kashiwamura, S., Yoshimoto, T. & Nakanishi, K. Interleukin-18: a novel cytokine that augments both innate and acquired immunity. Adv. Immunol. 70, 281–312 (1998).
  Article CAS PubMed Google Scholar
• Bazan, J. F., Timans, J. C. & Kastelein, R. A. A newly defined interleukin-1? Nature 379, 591 (1996).
  Article CAS PubMed Google Scholar
• Barbulescu, K. et al. IL-12 and IL-18 differentially regulate the transcriptional activity of the human IFN-γ promoter in primary CD4+ T lymphocytes. J. Immunol. 160, 3642–3647 (1998).
  CAS PubMed Google Scholar
• Nakahira, M. et al. Synergy of IL-12 and IL-18 for IFN-γ gene expression: IL-12-induced STAT4 contributes to IFN-γ promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1. J. Immunol. 168, 1146–1153 (2002).
  Article CAS PubMed Google Scholar
• Chang, J. T., Segal, B. M., Nakanishi, K., Okamura, H. & Shevach, E. M. The costimulatory effect of IL-18 on the induction of antigen-specific IFN-γ production by resting T cells is IL-12 dependent and is mediated by up-regulation of the IL-12 receptor β2-subunit. Eur. J. Immunol. 30, 1113–1119 (2000).
  Article CAS PubMed Google Scholar
• Nakanishi, K., Yoshimoto, T., Tsutsui, H. & Okamura, H. Interleukin-18 regulates both TH1 and TH2 responses. Annu. Rev. Immunol. 19, 423–474 (2001).
  Article CAS PubMed Google Scholar
• Yang, J., Murphy, T. L., Ouyang, W. & Murphy, K. M. Induction of interferon-γ production in TH1 CD4+ T cells: evidence for two distinct pathways for promoter activation. Eur. J. Immunol. 29, 548–555 (1999).
  Article CAS PubMed Google Scholar
• Wu, C. Y., Gadina, M., Wang, K., O'Shea, J. & Seder, R. A. Cytokine regulation of IL-12 receptor-β2 expression: differential effects on human T and NK cells. Eur. J. Immunol. 30, 1364–1374 (2000).
  Article CAS PubMed Google Scholar
• Sareneva, T., Julkunen, I. & Matikainen, S. IFN-α and IL-12 induce IL-18 receptor gene expression in human NK and T cells. J. Immunol. 165, 1933–1938 (2000).
  Article CAS PubMed Google Scholar
• Park, W. R. et al. CD28 costimulation is required not only to induce IL-12 receptor but also to render janus kinases/STAT4 responsive to IL-12 stimulation in TCR-triggered T cells. Eur. J. Immunol. 31, 1456–1464 (2001).
  Article CAS PubMed Google Scholar
• Elloso, M. M. & Scott, P. Differential requirement of CD28 for IL-12 receptor expression and function in CD4+ and CD8+ T cells. Eur. J. Immunol. 31, 384–395 (2001).
  Article CAS PubMed Google Scholar
• Carter, L. L. & Murphy, K. M. Lineage-specific requirement for signal transducer and activator of transcription (Stat)4 in interferon-γ production from CD4+ versus CD8+ T cells. J. Exp. Med. 189, 1355–1360 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Afonso, L. C. et al. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science 263, 235–237 (1994).
  Article CAS PubMed 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
• Manetti, R. et al. Interleukin-12 induces stable priming for interferon-γ (IFN-γ) production during differentiation of human T helper (TH) cells and transient IFN-γ production in established TH2-cell clones. J. Exp. Med. 179, 1273–1283 (1994).
  Article CAS PubMed Google Scholar
• Gerosa, F. et al. Interleukin-12 primes human CD4 and CD8 T-cell clones for high production of both interferon-γ and interleukin-10. J. Exp. Med. 183, 2559–2569 (1996).
  Article CAS PubMed Google Scholar
• Macatonia, S. E., Hsieh, C. S., Murphy, K. M. & O'Garra, A. Dendritic cells and macrophages are required for TH1 development of CD4+ T cells from αβ TCR transgenic mice: IL-12 substitution for macrophages to stimulate IFN-γ production is IFN-γ-dependent. Int. Immunol. 5, 1119–1128 (1993).
  Article CAS PubMed Google Scholar
• Noble, A., Thomas, M. J. & Kemeny, D. M. Early TH1/TH2 cell polarization in the absence of IL-4 and IL-12: T-cell receptor signaling regulates the response to cytokines in CD4 and CD8 T cells. Eur. J. Immunol. 31, 2227–2235 (2001).
  Article CAS PubMed Google Scholar
• Chen, Q. et al. Development of TH1-type immune responses requires the type I cytokine receptor TCCR. Nature 407, 916–920 (2000).
  Article CAS PubMed Google Scholar
• Szabo, S. J. et al. A novel transcription factor, T-bet, directs TH1 lineage commitment. Cell 100, 655–669 (2000). This study identifies the transcription factor T-bet as an important element in T H 1-cell commitment.
  Article CAS PubMed Google Scholar
• Mullen, A. C. et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292, 1907–1910 (2001). This paper shows that the appearance of T-bet in committed T H 1 cells precedes exposure to IL-12, indicating that IL-12 might have a role more in the fixation and amplification of T H 1 cells than in their commitment.
  Article CAS PubMed Google Scholar
• Heath, V. L. et al. Cutting edge: ectopic expression of the IL-12 receptor-β2 in developing and committed TH2 cells does not affect the production of IL-4 or induce the production of IFN-γ. J. Immunol. 164, 2861–2865 (2000).
  Article CAS PubMed Google Scholar
• Lighvani, A. A. et al. T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells. Proc. Natl Acad. Sci. USA 98, 15137–15142 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Afkarian, M. et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nature Immunol. 3, 549–557 (2002).
  Article CAS Google Scholar
• Szabo, S. J. et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-γ production in CD4 and CD8 T cells. Science 295, 338–342 (2002). This study characterizes the role of T-bet in T H 1-cell differentiation in vivo in mice that are genetically deficient for T-bet, identifying a requirement for T-bet for the differentiation of type-1 CD4+, but not CD8+, cells.
  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
• 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
• 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
• Devergne, O., Coulomb-L'Hermine, A., Capel, F., Moussa, M. & Capron, F. Expression of Epstein–Barr virus-induced gene 3, an interleukin-12 p40-related molecule, throughout human pregnancy: involvement of syncytiotrophoblasts and extravillous trophoblasts. Am. J. Pathol. 159, 1763–1776 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Christ, A. D. et al. An interleukin-12-related cytokine is up-regulated in ulcerative colitis but not in Crohn's disease. Gastroenterology 115, 307–313 (1998).
  Article CAS PubMed Google Scholar
• Huang, Q. et al. The plasticity of dendritic-cell responses to pathogens and their components. Science 294, 870–875 (2001).
  Article CAS PubMed Google Scholar
• Murphy, T. L., Cleveland, M. G., Kulesza, P., Magram, J. & Murphy, K. M. Regulation of interleukin-12 p40 expression through an NF-κB half-site. Mol. Cell. Biol. 15, 5258–5267 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Plevy, S. E., Gemberling, J. H. M., Hsu, S., Dorner, A. J. & Smale, S. T. Multiple control elements mediate activation of the murine and human interleukin-12 p40 promoters: evidence of functional synergy between C/EBP and Rel proteins. Mol. Cell. Biol. 17, 4572–4588 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Becker, C. et al. Regulation of IL-12 p40 promoter activity in primary human monocytes: roles of NF-κB, CCAAT/enhancer-binding protein-β, and PU. 1 and identification of a novel repressor element (GA-12) that responds to IL-4 and prostaglandin E(2). J. Immunol. 167, 2608–2618 (2001).
  Article CAS PubMed Google Scholar
• Gorgoni, B., Maritano, D., Marthyn, P., Righi, M. & Poli, V. C/EBPβ gene inactivation causes both impaired and enhanced gene expression and inverse regulation of IL-12 p40 and p35 mRNAs in macrophages. J. Immunol. 168, 4055–4062 (2002).
  Article CAS PubMed Google Scholar
• Gri, G., Savio, D., Trinchieri, G. & Ma, X. Synergistic regulation of the human interleukin-12 p40 promoter by NF-κB and Ets transcription factors in Epstein–Barr virus-transformed B cells and macrophages. J. Biol. Chem. 273, 6431–6438 (1998).
  Article CAS PubMed Google Scholar
• Salkowski, C. A. et al. IL-12 is dysregulated in macrophages from IRF-1 and IRF-2 knockout mice. J. Immunol. 163, 1529–1536 (1999).
  CAS PubMed Google Scholar
• Cappiello, M. G., Sutterwala, F. S., Trinchieri, G., Mosser, D. M. & Ma, X. Suppression of IL-12 transcription in macrophages following Fcγ receptor ligation. J. Immunol. 166, 4498–4506 (2001).
  Article CAS Google Scholar
• Wang, I. M. et al. An IFN-γ-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages. J. Immunol. 165, 271–279 (2000).
  Article CAS PubMed Google Scholar
• D'Ambrosio, D. et al. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene. J. Clin. Invest. 101, 252–262 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Delgado, M. & Ganea, D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit interleukin-12 transcription by regulating nuclear factor-κB and Ets activation. J. Biol. Chem. 274, 31930–31940 (1999).
  Article CAS PubMed Google Scholar
• Maruo, S. et al. IL-12 produced by antigen-presenting cells induces IL-2-independent proliferation of T-helper cell clones. J. Immunol. 156, 1748–1755 (1996).
  CAS PubMed Google Scholar
• Seder, R. A., Kelsall, B. L. & Jankovic, D. Differential roles for IL-12 in the maintenance of immune responses in infectious versus autoimmune disease. J. Immunol. 157, 2745–2748 (1996).
  CAS PubMed Google Scholar
• Yap, G., Pesin, M. & Sher, A. Cutting edge: IL-12 is required for the maintenance of IFN-γ production in T cells mediating chronic resistance to the intracellular pathogen Toxoplasma gondii. J. Immunol. 165, 628–631 (2000).
  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
• Orange, J. S., Wang, B., Terhorst, C. & Biron, C. A. Requirement for natural killer cell-produced interferon-γ in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin-12 administration. J. Exp. Med. 182, 1045–1056 (1995).
  Article CAS PubMed Google Scholar
• Monteiro, J. M., Harvey, C. & Trinchieri, G. Role of interleukin-12 in primary influenza virus infection. J. Virol. 72, 4825–4831 (1998).
  CAS PubMed PubMed Central Google Scholar
• Geng, Y., Berencsi, K., Gyulai, Z., Valgi-Nagy, T., Gonczol, E. & Trinchieri, G. Roles of interleukin-12 and interferon-γ in murine Chlamydia pneumoniae infection. Infect. Immun. 68, 2245–2253 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Penttila, J. M. et al. Local immune responses to Chlamydia pneumoniae in the lungs of BALB/c mice during primary infection and reinfection. Infect. Immun. 66, 5113–5118 (1998).
  CAS PubMed PubMed Central Google Scholar
• Rogge, L. et al. The role of Stat4 in species-specific regulation of TH-cell development by type I IFNs. J. Immunol. 161, 6567–6574 (1998).
  CAS PubMed Google Scholar
• Farrar, J. D. et al. Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2. Nature Immunol. 1, 65–69 (2000).
  Article CAS Google Scholar
• Matikainen, S. et al. IFN-α and IL-18 synergistically enhance IFN-γ production in human NK cells: differential regulation of Stat4 activation and IFN-γ gene expression by IFN-α and IL-12. Eur. J. Immunol. 31, 2236–2245 (2001).
  Article CAS PubMed Google Scholar
• Fallarino, F., Uyttenhove, C., Boon, T. & Gajewski, T. F. Endogenous IL-12 is necessary for rejection of P815 tumor variants in vivo. J. Immunol. 156, 1095–1100 (1996).
  CAS PubMed Google Scholar
• Smyth, M. J. et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191, 661–668 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Brunda, M. J. et al. Antitumor and antimetastatic activity of interleukin-12 against murine tumors. J. Exp. Med. 178, 1223–1230 (1993).
  Article CAS PubMed Google Scholar
• Noguchi, Y., Jungbluth, A., Richards, E. C. & Old, L. J. Effect of interleukin-12 on tumor induction by 3-methylcholanthrene. Proc. Natl Acad. Sci. USA 93, 11798–11801 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Nanni, P. et al. Combined allogeneic tumor-cell vaccination and systemic interleukin-12 prevents mammary carcinogenesis in HER-2/neu transgenic mice. J. Exp. Med. 194, 1195–1205 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Colombo, M. P. & Trinchieri, G. Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 13, 155–168 (2002).
  Article CAS PubMed Google Scholar
• Voest, E. E. et al. Inhibition of angiogenesis in vivo by interleukin-12. J. Natl Cancer Inst. 87, 581–586 (1995).
  Article CAS PubMed Google Scholar
• Yao, L. et al. Effective targeting of tumor vasculature by the angiogenesis inhibitors vasostatin and interleukin-12. Blood 96, 1900–1905 (2000).
  CAS PubMed Google Scholar
• Gee, M. S. et al. Doppler ultrasound imaging detects changes in tumor perfusion during antivascular therapy associated with vascular anatomic alterations. Cancer Res. 61, 2974–2982 (2001).
  CAS PubMed Google Scholar
• Quaglino, E. et al. Immunological prevention of spontaneous tumors: a new prospect? Immunol. Lett. 80, 75–79 (2002).
  Article CAS PubMed Google Scholar
• Taga, T. & Kishimoto, T. Gp130 and the interleukin-6 family of cytokines. Annu. Rev. Immunol. 15, 797–819 (1997).
  Article CAS PubMed Google Scholar
• Kawashima, T., Kawasaki, H., Kitamura, T., Nojima, Y. & Morimoto, C. Interleukin-12 induces tyrosine phosphorylation of an 85-kDa protein associated with the interleukin-12 receptor-β1 subunit. Cell. Immunol. 186, 39–44 (1998).
  Article CAS PubMed Google Scholar