Skip to main content

Advertisement

SpringerLink
Log in

The power of combinatorial immunology: IL-12 and IL-12-related dimeric cytokines in infectious diseases

  • Review
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Appropriate induction of a Th1 immune response is required for effective antimicrobial immunity. However, dysregulated Th1 immune responses after infection may also lead to immunopathology. Thus, cell-mediated immune responses have to be tightly regulated. Upon infection, the production of interleukin (IL)-12, a heterodimeric cytokine composed of a p35 and a p40 subunit, is the dominant factor in Th1 cell development. The recent discovery of novel dimeric cytokines closely related to IL-12 add now to our understanding of cellular immunity and the fine tuning of T cell responses. At the onset of infection, IL-27, a heterodimer composed of the IL-12p40-related protein EBI-3 (Epstein-Barr virus-induced gene 3) and the IL-12p35-related protein p28 induces the expression of a functional IL-12 receptor in naive CD4+ T cells, making these cells sensitive to IL-12-mediated Th cell development. Later during infection, IL-23, a heterodimer composed of the IL-12p40 subunit and the IL-12p35-related molecule p19, preferentially acts on Th1 effector/memory CD4+ T cells. The IL-12p40 subunit can also form a homodimer, IL-12p80, which act as an IL-12 and IL-23 antagonist by competing at their receptors. This review focuses on these IL-12-related cytokines contributing to fine tuning of T cell responses after infection with intracellular pathogens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.

Similar content being viewed by others

References

  1. Murphy KM, Ouyang W, Farrar JD, Yang J, Ranganath S, Asnagli H, Afkarian M, Murphy TL (2000) Signaling and transcription in T helper development. Annu Rev Immunol 18:451

    CAS  PubMed  Google Scholar 

  2. Glimcher LH, Murphy KM (2000) Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev 14:1693

    CAS  PubMed  Google Scholar 

  3. Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G (1989) Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 170:827

    CAS  PubMed  Google Scholar 

  4. Stern AS, Podlaski FJ, Hulmes JD, et al (1990) Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci USA 87:6808

    CAS  PubMed  Google Scholar 

  5. Gubler U, Chua AO, Schoenhaut DS, et al (1991) Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci USA 88:4143

    CAS  PubMed  Google Scholar 

  6. Wolf SF, Temple PA, Kobayashi M, et al (1991) 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

    CAS  PubMed  Google Scholar 

  7. Cooper AM, Magram J, Ferrante J, Orme IM (1997) Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis. J Exp Med 186:39

    CAS  PubMed  Google Scholar 

  8. Müller U, Köhler G, Mossmann H, Schaub GA, Alber G, Di Santo JP, Brombacher F, Hölscher C (2001) IL-12-independent IFN-gamma production by T cells in experimental Chagas' disease is mediated by IL-18. J Immunol 167:3346

    PubMed  Google Scholar 

  9. Mattner F, Magram J, Ferrante J, Launois P, Di Padova K, Behin R, Gately MK, Louis JA, Alber G (1996) 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

    CAS  PubMed  Google Scholar 

  10. Magram J, Connaughton SE, Warrier RR, Carvajal DM, Wu CY, Ferrante J, Stewart C, Sarmiento U, Faherty DA, Gately MK (1996) IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity 4:471

    CAS  PubMed  Google Scholar 

  11. Scharton-Kersten TM, Yap G, Magram J, Sher A (1997) 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

    Article  CAS  PubMed  Google Scholar 

  12. Magram J, Sfarra J, Connaughton S, Faherty D, Warrier R, Carvajal D, Wu CY, Stewart C, Sarmiento U, Gately MK (1996) IL-12-deficient mice are defective but not devoid of type 1 cytokine responses. Ann N Y Acad Sci 795:60

    CAS  PubMed  Google Scholar 

  13. Wu C, Ferrante J, Gately MK, Magram J (1997) Characterization of IL-12 receptor beta1 chain (IL-12Rbeta1)-deficient mice: IL-12Rbeta1 is an essential component of the functional mouse IL-12 receptor. J Immunol 159:1658

    CAS  PubMed  Google Scholar 

  14. Wu C, Wang X, Gadina M, O'Shea JJ, Presky DH, Magram J (2000) IL-12 receptor beta 2 (IL-12R beta 2)-deficient mice are defective in IL-12-mediated signaling despite the presence of high affinity IL-12 binding sites. J Immunol 165:6221

    CAS  PubMed  Google Scholar 

  15. Cooper AM, Kipnis A, Turner J, Magram J, Ferrante J, Orme IM (2002) 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

    CAS  PubMed  Google Scholar 

  16. Decken K, Kohler G, Palmer-Lehmann K, Wunderlin A, Mattner F, Magram J, Gately MK, Alber G (1998) Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans. Infect Immun 66:4994

    CAS  PubMed  Google Scholar 

  17. Elkins KL, Cooper A, Colombini SM, Cowley SC, Kieffer TL (2002) 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

    Article  CAS  PubMed  Google Scholar 

  18. Hölscher C, Atkinson RA, Arendse B, Brown N, Myburgh E, Alber G, Brombacher F (2001) A protective and agonistic function of IL-12p40 in mycobacterial infection. J Immunol 167:6957

    PubMed  Google Scholar 

  19. Lehmann J, Bellmann S, Werner C, Schroder R, Schutze N, Alber G (2001) IL-12p40-dependent agonistic effects on the development of protective innate and adaptive immunity against Salmonella enteritidis. J Immunol 167:5304

    CAS  PubMed  Google Scholar 

  20. Schoenhaut DS, Chua AO, Wolitzky AG, Quinn PM, Dwyer CM, McComas W, Familletti PC, Gately MK, Gubler U (1992) Cloning and expression of murine IL-12. J Immunol 148:3433

    CAS  PubMed  Google Scholar 

  21. Gearing DP, Cosman D (1991) Homology of the p40 subunit of natural killer cell stimulatory factor (NKSF) with the extracellular domain of the interleukin-6 receptor. Cell 66:9

    CAS  PubMed  Google Scholar 

  22. Podlaski FJ, Nanduri VB, Hulmes JD, Pan YC, Levin W, Danho W, Chizzonite R, Gately MK, Stern AS (1992) Molecular characterization of interleukin 12. Arch Biochem Biophys 294:230

    CAS  PubMed  Google Scholar 

  23. Sieburth D, Jabs EW, Warrington JA, Li X, Lasota J, LaForgia S, Kelleher K, Huebner K, Wasmuth JJ, Wolf SF (1992) Assignment of genes encoding a unique cytokine (IL12) composed of two unrelated subunits to chromosomes 3 and 5. Genomics 14:59

    CAS  PubMed  Google Scholar 

  24. Schweitzer PA, Noben-Trauth N, Pelsue SC, Johnson KR, Wolf SF, Shultz LD (1996) Genetic mapping of the IL-12 alpha chain gene (Il12a) on mouse chromosome 3. Mamm Genome 7:394

    Article  CAS  PubMed  Google Scholar 

  25. Trinchieri G (1994) Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood 84:4008

    CAS  PubMed  Google Scholar 

  26. Noben-Trauth N, Schweitzer PA, Johnson KR, Wolf SF, Knowles BB, Shultz LD (1996) The interleukin-12 beta subunit (p40) maps to mouse chromosome 11. Mamm Genome 7:392

    Article  CAS  PubMed  Google Scholar 

  27. Merberg DM, Wolf SF, Clark SC (1992) Sequence similarity between NKSF and the IL-6/G-CSF family. Immunol Today 13:77

    Article  CAS  Google Scholar 

  28. Ling P, Gately MK, Gubler U, Stern AS, Lin P, Hollfelder K, Su C, Pan YC, Hakimi J (1995) Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity. J Immunol 154:116

    CAS  PubMed  Google Scholar 

  29. Gillessen S, Carvajal D, Ling P, Podlaski FJ, Stremlo DL, Familletti PC, Gubler U, Presky DH, Stern AS, Gately MK (1995) Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist. Eur J Immunol 25:200

    CAS  PubMed  Google Scholar 

  30. Gately MK, Carvajal DM, Connaughton SE, Gillessen S, Warrier RR, Kolinsky KD, Wilkinson VL, Dwyer CM, Higgins GF Jr, Podlaski FJ, Faherty DA, Familletti PC, Stern AS, Presky DH (1996) Interleukin-12 antagonist activity of mouse interleukin-12 p40 homodimer in vitro and in vivo. Ann N Y Acad Sci 795:1

    CAS  PubMed  Google Scholar 

  31. Piccotti JR, Li K, Chan SY, Ferrante J, Magram J, Eichwald EJ, Bishop DK (1998) Alloantigen-reactive Th1 development in IL-12-deficient mice. J Immunol 160:1132

    CAS  PubMed  Google Scholar 

  32. Desai BB, Quinn PM, Wolitzky AG, Mongini PK, Chizzonite R, Gately MK (1992) IL-12 receptor. II. Distribution and regulation of receptor expression. J Immunol 148:3125

    CAS  PubMed  Google Scholar 

  33. Chua AO, Chizzonite R, Desai BB, et al (1994) Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gp130. J Immunol 153:128

    CAS  PubMed  Google Scholar 

  34. Chua AO, Wilkinson VL, Presky DH, Gubler U (1995) Cloning and characterization of a mouse IL-12 receptor-beta component. J Immunol 155:4286

    CAS  PubMed  Google Scholar 

  35. Presky DH, Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, Gately MK, Gubler U (1996) A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proc Natl Acad Sci USA 93:14002

    CAS  PubMed  Google Scholar 

  36. Wilkinson VL, Carvajal D, Minetti LJ, Chua AO, Gubler U, Gately MK, Presky DH (1997) Functional characterization of mouse IL-12 receptors. J.Allergy Clin Immunol 99:S52

    Google Scholar 

  37. Zou JP, Yamamoto N, Fujii T, Takenaka H, Kobayashi M, Herrmann SH, Wolf SF, Fujiwara H, Hamaoka T (1995) Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFN-gamma production by anti-tumor T cells. Int Immunol 7:1135

    CAS  PubMed  Google Scholar 

  38. Bacon CM, McVicar DW, Ortaldo JR, Rees RC, O'Shea JJ, Johnston JA (1995) Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med 181:399

    CAS  PubMed  Google Scholar 

  39. Bacon CM, Petricoin EF 3rd, Ortaldo JR, Rees RC, Larner AC, Johnston JA, O'Shea JJ (1995) Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc Natl Acad Sci USA 92:7307

    CAS  PubMed  Google Scholar 

  40. Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE Jr, Murphy KM (1995) Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med 181:1755

    CAS  PubMed  Google Scholar 

  41. Naeger LK, McKinney J, Salvekar A, Hoey T (1999) Identification of a STAT4 binding site in the interleukin-12 receptor required for signaling. J Biol Chem 274:1875

    Article  CAS  PubMed  Google Scholar 

  42. Yao BB, Niu P, Surowy CS, Faltynek CR (1999) Direct interaction of STAT4 with the IL-12 receptor. Arch Biochem Biophys 368:147

    Article  CAS  PubMed  Google Scholar 

  43. Benjamin D, Sharma V, Kubin M, Klein JL, Sartori A, Holliday J, Trinchieri G (1996) IL-12 expression in AIDS-related lymphoma B cell lines. J Immunol 156:1626

    CAS  PubMed  Google Scholar 

  44. Rogge L, Barberis-Maino L, Biffi M, Passini N, Presky DH, Gubler U, Sinigaglia F (1997) Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J Exp Med 185:825

    CAS  PubMed  Google Scholar 

  45. Wu C, Warrier RR, Wang X, Presky DH, Gately MK (1997) Regulation of interleukin-12 receptor beta1 chain expression and interleukin-12 binding by human peripheral blood mononuclear cells. Eur J Immunol 27:147

    CAS  PubMed  Google Scholar 

  46. Diefenbach A, Schindler H, Rollinghoff M, Yokoyama WM, Bogdan C (1999) Requirement for type 2 NO synthase for IL-12 signaling in innate immunity. Science 284:951

    Article  CAS  PubMed  Google Scholar 

  47. Trinchieri G (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 13:251

    CAS  PubMed  Google Scholar 

  48. Reiling N, Hölscher C, Fehrenbach A, Kröger S, Kirschning CJ, Goyert S, Ehlers S (2002) Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J Immunol 169:3480

    CAS  PubMed  Google Scholar 

  49. Medzhitov R, Janeway CA Jr (1997) Innate immunity: impact on the adaptive immune response. Curr Opin Immunol 9:4

    Article  CAS  PubMed  Google Scholar 

  50. Ma X, Trinchieri G (2001) Regulation of interleukin-12 production in antigen-presenting cells. Adv Immunol 79:55

    CAS  PubMed  Google Scholar 

  51. De Jong R, Altare F, Haagen IA, Elferink DG, Boer T, Breda Vriesman PJ van, Kabel PJ, Draaisma JM, Dissel JT van, Kroon FP, Casanova JL, Ottenhoff TH (1998) Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 280:1435

    PubMed  Google Scholar 

  52. Altare F, Durandy A, Lammas D, Emile JF, Lamhamedi S, Le Deist F, Drysdale P, Jouanguy E, Doffinger R, Bernaudin F, Jeppsson O, Gollob JA, Meinl E, Segal AW, Fischer A, Kumararatne D, Casanova JL (1998) Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280:1432

    CAS  PubMed  Google Scholar 

  53. Raupach B, Kaufmann SH (2001) Immune responses to intracellular bacteria. Curr Opin Immunol 13:417

    Article  CAS  PubMed  Google Scholar 

  54. Hölscher C, Köhler G, Müller U, Mossmann H, Schaub GA, Brombacher F (1998) Defective nitric oxide effector functions lead to extreme susceptibility of Trypanosoma cruzi-infected mice deficient in gamma interferon receptor or inducible nitric oxide synthase. Infect Immun 66:1208

    PubMed  Google Scholar 

  55. Brombacher F, Dorfmuller A, Magram J, Dai WJ, Kohler G, Wunderlin A, Palmer-Lehmann K, Gately MK, Alber G (1999) IL-12 is dispensable for innate and adaptive immunity against low doses of Listeria monocytogenes. Int Immunol 11:325

    Article  CAS  PubMed  Google Scholar 

  56. Rogge L, D'Ambrosio D, Biffi M, Penna G, Minetti LJ, Presky DH, Adorini L, Sinigaglia F (1998) The role of Stat4 in species-specific regulation of Th cell development by type I IFNs. J Immunol 161:6567

    CAS  PubMed  Google Scholar 

  57. Cousens LP, Peterson R, Hsu S, Dorner A, Altman JD, Ahmed R, Biron CA (1999) Two roads diverged: interferon alpha/beta- and interleukin 12-mediated pathways in promoting T cell interferon gamma responses during viral infection. J Exp Med 189:1315

    Article  CAS  PubMed  Google Scholar 

  58. Takeda K, Tsutsui H, Yoshimoto T, Adachi O, Yoshida N, Kishimoto T, Okamura H, Nakanishi K, Akira S (1998) Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 8:383

    CAS  PubMed  Google Scholar 

  59. Okamura H, Tsutsi H, Komatsu T, et al. (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378:88

    CAS  PubMed  Google Scholar 

  60. Freudenberg MA, Merlin T, Kalis C, Chvatchko Y, Stubig H, Galanos C (2002) Cutting edge: a murine, IL-12-independent pathway of IFN-gamma induction by gram-negative bacteria based on STAT4 activation by Type I IFN and IL-18 signaling. J Immunol 169:1665

    CAS  PubMed  Google Scholar 

  61. Satoskar AR, Rodig S, Telford SR 3rd, Satoskar AA, Ghosh SK, Lichtenberg F von, David JR (2000) IL-12 gene-deficient C57BL/6 mice are susceptible to Leishmania donovani but have diminished hepatic immunopathology. Eur J Immunol 30:834

    Article  CAS  PubMed  Google Scholar 

  62. Ely KH, Kasper LH, Khan IA (1999) Augmentation of the CD8+ T cell response by IFN-gamma in IL-12-deficient mice during Toxoplasma gondii infection. J Immunol 162:5449

    CAS  PubMed  Google Scholar 

  63. Kawakami K, Koguchi Y, Qureshi MH, Miyazato A, Yara S, Kinjo Y, Iwakura Y, Takeda K, Akira S, Kurimoto M, Saito A (2000) IL-18 contributes to host resistance against infection with Cryptococcus neoformans in mice with defective IL-12 synthesis through induction of IFN-gamma production by NK cells. J Immunol 165:941

    CAS  PubMed  Google Scholar 

  64. Wakeham J, Wang J, Magram J, Croitoru K, Harkness R, Dunn P, Zganiacz A, Xing Z (1998) Lack of both types 1 and 2 cytokines, tissue inflammatory responses, and immune protection during pulmonary infection by Mycobacterium bovis bacille Calmette-Guerin in IL-12-deficient mice. J Immunol 160:6101

    CAS  PubMed  Google Scholar 

  65. Schijns VE, Haagmans BL, Wierda CM, Kruithof B, Heijnen IA, Alber G, Horzinek MC (1998) Mice lacking IL-12 develop polarized Th1 cells during viral infection. J Immunol 160:3958

    CAS  PubMed  Google Scholar 

  66. Oxenius A, Karrer U, Zinkernagel RM, Hengartner H (1999) IL-12 is not required for induction of type 1 cytokine responses in viral infections. J Immunol 162:965

    CAS  PubMed  Google Scholar 

  67. Xing Z, Zganiacz A, Wang J, Divangahi M, Nawaz F (2000) IL-12-independent Th1-type immune responses to respiratory viral infection: requirement of IL-18 for IFN-gamma release in the lung but not for the differentiation of viral-reactive Th1-type lymphocytes. J Immunol 164:2575

    CAS  PubMed  Google Scholar 

  68. Stobie L, Gurunathan S, Prussin C, Sacks DL, Glaichenhaus N, Wu CY, Seder RA (2000) The role of antigen and IL-12 in sustaining Th1 memory cells in vivo: IL-12 is required to maintain memory/effector Th1 cells sufficient to mediate protection to an infectious parasite challenge. Proc Natl Acad Sci USA 97:8427

    CAS  PubMed  Google Scholar 

  69. Constantinescu CS, Hondowicz BD, Elloso MM, Wysocka M, Trinchieri G, Scott P (1998) The role of IL-12 in the maintenance of an established Th1 immune response in experimental leishmaniasis. Eur J Immunol 28:2227

    Article  CAS  PubMed  Google Scholar 

  70. Cleary AM, Tu W, Enright A, Giffon T, Dewaal-Malefyt R, Gutierrez K, Lewis DB (2003) Impaired accumulation and function of memory CD4 T cells in human IL-12 receptor beta1 deficiency. J Immunol 170:597

    CAS  PubMed  Google Scholar 

  71. Elgin GR (2003) Severe Mycobacterium bovis BCG infections in a large series of novel IL-12 receptor beta 1-deficient patients and evidence for the existence of partial receptor beta 1 deficiencies. Eur J Immunol 33:59

    Article  PubMed  Google Scholar 

  72. Verhagen CE, Boer T de, Smits HH, Verreck FA, Wierenga EA, Kurimoto M, Lammas DA, Kumararatne DS, Sanal O, Kroon FP, Dissel JT van, Sinigaglia F, Ottenhoff TH (2000) Residual type 1 immunity in patients genetically deficient for interleukin 12 receptor beta1 (IL-12Rbeta1): evidence for an IL-12Rbeta1-independent pathway of IL-12 responsiveness in human T cells. J Exp Med 192:517

    Article  CAS  PubMed  Google Scholar 

  73. Piccotti JR, Chan SY, Li K, Eichwald EJ, Bishop DK (1997) Differential effects of IL-12 receptor blockade with IL-12 p40 homodimer on the induction of CD4+ and CD8+ IFN-gamma-producing cells. J Immunol 158:643

    CAS  PubMed  Google Scholar 

  74. D'Andrea A, Rengaraju M, Valiante NM, et al (1992) Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med 176:1387

    CAS  PubMed  Google Scholar 

  75. Heinzel FP, Hujer AM, Ahmed FN, Rerko RM (1997) In vivo production and function of IL-12 p40 homodimers. J Immunol 158:4381

    CAS  PubMed  Google Scholar 

  76. Mattner F, Ozmen L, Podlaski FJ, Wilkinson VL, Presky DH, Gately MK, Alber G (1997) Treatment with homodimeric interleukin-12 (IL-12) p40 protects mice from IL-12-dependent shock but not from tumor necrosis factor alpha-dependent shock. Infect Immun 65:4734

    CAS  PubMed  Google Scholar 

  77. Kato K, Shimozato O, Hoshi K, Wakimoto H, Hamada H, Yagita H, Okumura K (1996) Local production of the p40 subunit of interleukin 12 suppresses T-helper 1-mediated immune responses and prevents allogeneic myoblast rejection. Proc Natl Acad Sci USA 93:9085

    Article  CAS  PubMed  Google Scholar 

  78. Zou J, Presky DH, Wu CY, Gubler U (1997) Differential associations between the cytoplasmic regions of the interleukin-12 receptor subunits beta1 and beta2 and JAK kinases. J Biol Chem 272:6073

    Article  CAS  PubMed  Google Scholar 

  79. Kawashima T, Kawasaki H, Kitamura T, Nojima Y, Morimoto C (1998) Interleukin-12 induces tyrosine phosphorylation of an 85-kDa protein associated with the interleukin-12 receptor beta 1 subunit. Cell Immunol 186:39

    Article  CAS  PubMed  Google Scholar 

  80. Lankford CS, Frucht DM (2003) A unique role for IL-23 in promoting cellular immunity. J Leukoc Biol 73:49

    Article  CAS  PubMed  Google Scholar 

  81. 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, Waal-Malefyt R de, 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

    CAS  PubMed  Google Scholar 

  82. 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, Waal Malefyt R de, Moore KW (2002) A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 168:5699

    CAS  PubMed  Google Scholar 

  83. Ihle JN (2001) The Stat family in cytokine signaling. Curr Opin Cell Biol 13:211

    CAS  PubMed  Google Scholar 

  84. Darnell JE Jr (1997) STATs and gene regulation. Science 277:1630

    CAS  PubMed  Google Scholar 

  85. Wiekowski MT, Leach MW, Evans EW, Sullivan L, Chen SC, Vassileva G, Bazan JF, Gorman DM, Kastelein RA, Narula S, Lira SA (2001) Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J Immunol 166:7563

    CAS  PubMed  Google Scholar 

  86. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744

    Article  CAS  PubMed  Google Scholar 

  87. Ehlers S, Benini J, Held HD, Roeck C, Alber G, Uhlig S (2001) Alphabeta T cell receptor-positive cells and interferon-gamma, but not inducible nitric oxide synthase, are critical for granuloma necrosis in a mouse model of mycobacteria-induced pulmonary immunopathology. J Exp Med 194:1847

    Article  CAS  PubMed  Google Scholar 

  88. Frucht DM, Fukao T, Bogdan C, Schindler H, O'Shea JJ, Koyasu S (2001) IFN-gamma production by antigen-presenting cells: mechanisms emerge. Trends Immunol 22:556

    Article  CAS  PubMed  Google Scholar 

  89. Fukao T, Frucht DM, Yap G, Gadina M, O'Shea JJ, Koyasu S (2001) Inducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses. J Immunol 166:4446

    CAS  PubMed  Google Scholar 

  90. Belladonna ML, Renauld JC, Bianchi R, Vacca C, Fallarino F, Orabona C, Fioretti MC, Grohmann U, Puccetti P (2002) IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells. J Immunol 168:5448

    CAS  PubMed  Google Scholar 

  91. Liebermann LA, Cardillo F, Rennick D, Hunter CA (2002) IL-12-independent mechanisms of resistance during T. gondii infection: a role for IL-23? FASEB J 16:Q1068

  92. 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

    CAS  PubMed  Google Scholar 

  93. 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, Waal Malefyt R de, 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

    Google Scholar 

  94. 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

    CAS  PubMed  Google Scholar 

  95. 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 407:916

    Article  CAS  PubMed  Google Scholar 

  96. 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

    Article  CAS  PubMed  Google Scholar 

  97. 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 (in press)

    Google Scholar 

  98. Nieuwenhuis EE, Neurath MF, Corazza N, Iijima H, Trgovcich J, Wirtz S, Glickman J, Bailey D, Yoshida M, Galle PR, Kronenberg M, Birkenbach M, Blumberg RS (2002) Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice. Proc Natl Acad Sci USA 99:16951

    Article  CAS  PubMed  Google Scholar 

  99. Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383:787

    Google Scholar 

  100. Fearon DT, Locksley RM (1996) The instructive role of innate immunity in the acquired immune response. Science 272:50

    CAS  PubMed  Google Scholar 

  101. Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17:629

    CAS  PubMed  Google Scholar 

  102. Boirivant M, Fuss IJ, Chu A, Strober W (1998) Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med 188:1929

    Article  CAS  PubMed  Google Scholar 

  103. Devergne O, Coulomb-L'Hermine A, Capel F, Moussa M, Capron F (2001) 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

    CAS  PubMed  Google Scholar 

  104. Snijders A, Hilkens CM, Pouw Kraan TC van der, Engel M, Aarden LA, Kapsenberg ML (1996) Regulation of bioactive IL-12 production in lipopolysaccharide-stimulated human monocytes is determined by the expression of the p35 subunit. J Immunol 156:1207

    CAS  PubMed  Google Scholar 

  105. Bette M, Jin SC, Germann T, Schafer MK, Weihe E, Rude E, Fleischer B (1994) Differential expression of mRNA encoding interleukin-12 p35 and p40 subunits in situ. Eur J Immunol 24:2435

    CAS  PubMed  Google Scholar 

  106. Reis e Sousa C, Hieny S, Scharton-Kersten T, Jankovic D, Charest H, Germain RN, Sher A (1997) 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

    Article  PubMed  Google Scholar 

  107. Scharton-Kersten TM, Wynn TA, Denkers EY, Bala S, Grunvald E, Hieny S, Gazzinelli RT, Sher A (1996) In the absence of endogenous IFN-gamma, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. J Immunol 157:4045

    CAS  PubMed  Google Scholar 

  108. Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, Caspar P, Trinchieri G, Sher A (1994) Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol 153:2533

    CAS  PubMed  Google Scholar 

  109. Grumont R, Hochrein H, O'Keeffe M, Gugasyan R, White C, Caminschi I, Cook W, Gerondakis S (2001) c-Rel regulates interleukin 12 p70 expression in CD8(+) dendritic cells by specifically inducing p35 gene transcription. J Exp Med 194:1021

    Article  CAS  PubMed  Google Scholar 

  110. Braun MC, Lahey E, Kelsall BL (2000) Selective suppression of IL-12 production by chemoattractants. J Immunol 164:3009

    CAS  PubMed  Google Scholar 

  111. Pirhonen J, Matikainen S, Julkunen I (2002) Regulation of virus-induced IL-12 and IL-23 expression in human macrophages. J Immunol 169:5673

    CAS  PubMed  Google Scholar 

  112. Re F, Strominger JL (2001) Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J Biol Chem 276:37692

    CAS  PubMed  Google Scholar 

  113. Hayes MP, Murphy FJ, Burd PR (1998) Interferon-gamma-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

    CAS  PubMed  Google Scholar 

  114. Ma X, Chow JM, Gri G, Carra G, Gerosa F, Wolf SF, Dzialo R, Trinchieri G (1996) The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. J Exp Med 183:147

    CAS  PubMed  Google Scholar 

  115. D'Andrea A, Ma X, Aste-Amezaga M, Paganin C, Trinchieri G (1995) 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 alpha production. J Exp Med 181:537

    CAS  PubMed  Google Scholar 

  116. Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G (1996) 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

    CAS  PubMed  Google Scholar 

  117. Kalinski P, Smits HH, Schuitemaker JH, Vieira PL, Eijk M van, Jong EC de, Wierenga EA, Kapsenberg ML (2000) 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

    CAS  PubMed  Google Scholar 

  118. Macatonia SE, Hosken NA, Litton M, Vieira P, Hsieh CS, Culpepper JA, Wysocka M, Trinchieri G, Murphy KM, O'Garra A (1995) Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol 154:5071

    CAS  PubMed  Google Scholar 

  119. Schulz O, Edwards AD, Schito M, Aliberti J, Manickasingham S, Sher A, Reis e Sousa C (2000) CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity 13:453

    CAS  PubMed  Google Scholar 

  120. Weinmann AS, Plevy SE, Smale ST (1999) Rapid and selective remodeling of a positioned nucleosome during the induction of IL-12 p40 transcription. Immunity 11:665

    CAS  PubMed  Google Scholar 

  121. Weinmann AS, Mitchell DM, Sanjabi S, Bradley MN, Hoffmann A, Liou HC, Smale ST (2001) Nucleosome remodeling at the IL-12 p40 promoter is a TLR-dependent, Rel-independent event. Nat Immunol 2:51

    Article  CAS  PubMed  Google Scholar 

  122. Eaves-Pyles T, Murthy K, Liaudet L, Virag L, Ross G, Soriano FG, Szabo C, Salzman AL (2001) Flagellin, a novel mediator of Salmonella-induced epithelial activation and systemic inflammation: I kappa B alpha degradation, induction of nitric oxide synthase, induction of proinflammatory mediators, and cardiovascular dysfunction. J Immunol 166:1248

    CAS  PubMed  Google Scholar 

  123. Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, Ghosh S, Janeway CA Jr (1998) MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 2:253

    CAS  PubMed  Google Scholar 

  124. Takeuchi O, Kaufmann A, Grote K, Kawai T, Hoshino K, Morr M, Muhlradt PF, Akira S (2000) Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2- and MyD88-dependent signaling pathway. J Immunol 164:554

    CAS  PubMed  Google Scholar 

  125. Kawai T, Adachi O, Ogawa T, Takeda K, Akira S (1999) Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115

    CAS  PubMed  Google Scholar 

  126. Rudolph D, Yeh WC, Wakeham A, Rudolph B, Nallainathan D, Potter J, Elia AJ, Mak TW (2000) Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. Genes Dev 14:854

    CAS  PubMed  Google Scholar 

  127. Schmidt-Supprian M, Bloch W, Courtois G, Addicks K, Israel A, Rajewsky K, Pasparakis M (2000) NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Mol Cell 5:981

    CAS  PubMed  Google Scholar 

  128. Chu WM, Ostertag D, Li ZW, Chang L, Chen Y, Hu Y, Williams B, Perrault J, Karin M (1999) JNK2 and IKKbeta are required for activating the innate response to viral infection. Immunity 11:721

    CAS  PubMed  Google Scholar 

  129. Plevy SE, Gemberling JH, Hsu S, Dorner AJ, Smale ST (1997) 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

    CAS  PubMed  Google Scholar 

  130. An MR, Hsieh CC, Reisner PD, Rabek JP, Scott SG, Kuninger DT, Papaconstantinou J (1996) Evidence for posttranscriptional regulation of C/EBPalpha and C/EBPbeta isoform expression during the lipopolysaccharide-mediated acute-phase response. Mol Cell Biol 16:2295

    CAS  PubMed  Google Scholar 

  131. Descombes P, Schibler U (1991) A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA. Cell 67:569

    CAS  PubMed  Google Scholar 

  132. Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, Bleharski JR, Maitland M, Norgard MV, Plevy SE, Smale ST, Brennan PJ, Bloom BR, Godowski PJ, Modlin RL (1999) Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285:732

    Article  CAS  PubMed  Google Scholar 

  133. Screpanti I, Romani L, Musiani P, et al. (1995) Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice. EMBO J 14:1932

    CAS  PubMed  Google Scholar 

  134. Tanaka T, Akira S, Yoshida K, Umemoto M, Yoneda Y, Shirafuji N, Fujiwara H, Suematsu S, Yoshida N, Kishimoto T (1995) Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages. Cell 80:353

    CAS  PubMed  Google Scholar 

  135. Gorgoni B, Maritano D, Marthyn P, Righi M, Poli V (2002) C/EBP beta 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

    CAS  PubMed  Google Scholar 

  136. Ma X, Neurath M, Gri G, Trinchieri G (1997) 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

    Article  CAS  PubMed  Google Scholar 

  137. Gri G, Savio D, Trinchieri G, Ma X (1998) Synergistic regulation of the human interleukin-12 p40 promoter by NFkappaB and Ets transcription factors in Epstein-Barr virus-transformed B cells and macrophages. J Biol Chem 273:6431

    Article  CAS  PubMed  Google Scholar 

  138. Salkowski CA, Kopydlowski K, Blanco J, Cody MJ, McNally R, Vogel SN (1999) IL-12 is dysregulated in macrophages from IRF-1 and IRF-2 knockout mice. J Immunol 163:1529

    CAS  PubMed  Google Scholar 

  139. Grazia Cappiello M, Sutterwala FS, Trinchieri G, Mosser DM, Ma X (2001) Suppression of Il-12 transcription in macrophages following Fc gamma receptor ligation. J Immunol 166:4498

    PubMed  Google Scholar 

  140. Kubin M, Chow JM, Trinchieri G (1994) Differential regulation of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-1 beta production in human myeloid leukemia cell lines and peripheral blood mononuclear cells. Blood 83:1847

    CAS  PubMed  Google Scholar 

  141. Hayes MP, Wang J, Norcross MA (1995) Regulation of interleukin-12 expression in human monocytes: selective priming by interferon-gamma of lipopolysaccharide-inducible p35 and p40 genes. Blood 86:646

    CAS  PubMed  Google Scholar 

  142. Tone Y, Thompson SA, Babik JM, Nolan KF, Tone M, Raven C, Waldmann H (1996) Structure and chromosomal location of the mouse interleukin-12 p35 and p40 subunit genes. Eur J Immunol 26:1222

    CAS  PubMed  Google Scholar 

  143. Yoshimoto T, Kojima K, Funakoshi T, Endo Y, Fujita T, Nariuchi H (1996) Molecular cloning and characterization of murine IL-12 genes. J Immunol 156:1082

    CAS  PubMed  Google Scholar 

  144. Hochrein H, O'Keeffe M, Luft T, Vandenabeele S, Grumont RJ, Maraskovsky E, Shortman K (2000) Interleukin (IL)-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J Exp Med 192:823

    Article  CAS  PubMed  Google Scholar 

  145. Carra G, Gerosa F, Trinchieri G (2000) Biosynthesis and posttranslational regulation of human IL-12. J Immunol 164:4752

    CAS  PubMed  Google Scholar 

  146. Murphy FJ, Hayes MP, Burd PR (2000) Disparate intracellular processing of human IL-12 preprotein subunits: atypical processing of the P35 signal peptide. J Immunol 164:839

    CAS  PubMed  Google Scholar 

  147. Martens E, Alloza I, Scott CJ, Billiau A, Vandenbroeck K (2000) Protein disulfide isomerase-mediated cell-free assembly of recombinant interleukin-12 p40 homodimers. Eur J Biochem 267:6679

    Article  CAS  PubMed  Google Scholar 

  148. Aste-Amezaga M, Ma X, Sartori A, Trinchieri G (1998) Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J Immunol 160:5936

    CAS  PubMed  Google Scholar 

  149. D'Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G (1993) Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med 178:1041

    CAS  PubMed  Google Scholar 

  150. Brombacher F (2000) The role of interleukin-13 in infectious diseases and allergy. Bioessays 22:646

    Article  CAS  PubMed  Google Scholar 

  151. Du C, Sriram S (1998) Mechanism of inhibition of LPS-induced IL-12p40 production by IL-10 and TGF-beta in ANA-1 cells. J Leukoc Biol 64:92

    CAS  PubMed  Google Scholar 

  152. Braun MC, Kelsall BL (2001) Regulation of interleukin-12 production by G-protein-coupled receptors. Microbes Infect 3:99

    Article  CAS  PubMed  Google Scholar 

  153. Jankovic D, Kullberg MC, Hieny S, Caspar P, Collazo CM, Sher A (2002) 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

    CAS  PubMed  Google Scholar 

  154. Belkaid Y, Hoffmann KF, Mendez S, Kamhawi S, Udey MC, Wynn TA, Sacks DL (2001) 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

    Article  CAS  PubMed  Google Scholar 

  155. Hölscher C, Mohrs M, Dai WJ, Köhler G, Ryffel B, Schaub GA, Mossmann H, Brombacher F (2000) Tumor necrosis factor alpha-mediated toxic shock in Trypanosoma cruzi-infected interleukin 10-deficient mice. Infect Immun 68:4075

    Article  PubMed  Google Scholar 

  156. Hölscher C (2003) Interleukin-13: genes, receptors and signal transduction. In: Brombacher F (ed) Interleukin-13. Lands Bioscience, Georgetown, p 1

  157. Becker C, Wirtz S, Ma X, Blessing M, Galle PR, Neurath MF (2001) Regulation of IL-12 p40 promoter activity in primary human monocytes: roles of NF-kappaB, CCAAT/enhancer-binding protein beta, 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

    CAS  PubMed  Google Scholar 

  158. O'Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8:275

    CAS  PubMed  Google Scholar 

  159. Yoon C, Johnston SC, Tang J, Stahl M, Tobin JF, Somers WS (2000) Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12. EMBO J 19:3530

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Thanks to Alexandra Hölscher for technical assistance in IL-12-related projects and to Stefan Ehlers for critically reading the manuscript and fruitful discussions.

Author information

Authors and Affiliations

  1. Junior Research Group Molecular Infection Biology, Research Center Borstel, Parkallee 22, 23845, Borstel, Germany

    Christoph Hölscher

Authors
  1. Christoph Hölscher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christoph Hölscher.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hölscher, C. The power of combinatorial immunology: IL-12 and IL-12-related dimeric cytokines in infectious diseases. Med Microbiol Immunol 193, 1–17 (2004). https://doi.org/10.1007/s00430-003-0186-x

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-003-0186-x

Keywords

Search

Navigation