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Interleukin-12

  • Howard L. Kaufman
  • Neal Dharmadhikari
Living reference work entry

Abstract

Interleukin-12 (IL-12) is a heterodimeric cytokine and is a member of the larger family of IL-12-related cytokines. The other members of the IL-12 family include IL-23, IL-27, and IL-35. While IL-12 shares numerous structural features and molecular receptors with other members of its family, IL-12 is functionally unique (Vignali and Kuchroo 2012). IL-12 was first recovered from an Epstein-Barr virus-transformed B lymphoblastoid cell line in 1989 as “natural killer-stimulating factor” (Kobayashi et al. 1989). The following year, a separate group independently discovered IL-12 as “cytotoxic lymphocyte maturation factor” (Stern et al. 1990). Since its discovery, a tremendous amount of research has been conducted to characterize the physiologic function of IL-12 and assess therapeutic potential of agonist and antagonistic targeting of IL-12 for the treatment of a variety of diseases.

Keywords

Interleukin-12 Biology Clinical summary Diagnostics Preclinical summary Target assessment 

References

  1. Ansell SM, Witzig TE, Kurtin PJ, et al. Phase 1 study of interleukin-12 in combination with rituximab in patients with B-cell non-Hodgkin lymphoma. Blood. 2002;99:67–74.CrossRefPubMedGoogle Scholar
  2. Anwer K, Barnes MN, Fewell J, Lewis DH, Alvarez RD. Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer. Gene Ther. 2010;17:360–9.CrossRefPubMedGoogle Scholar
  3. Anwer K, Kelly FJ, Chu C, Fewell JG, Lewis D, Alvarez RD. Phase I trial of a formulated IL-12 plasmid in combination with carboplatin and docetaxel chemotherapy in the treatment of platinum-sensitive recurrent ovarian cancer. Gynecol Oncol. 2013;131:169–73.CrossRefPubMedGoogle Scholar
  4. Atkins MB, Robertson MJ, Gordon M, et al. Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res. 1997;3:409–17.PubMedGoogle Scholar
  5. Avigan D, Rosenblatt J, Kufe D. Dendritic/tumor fusion cells as cancer vaccines. Semin Oncol. 2012;39:287–95.CrossRefPubMedGoogle Scholar
  6. Bonnema JD, Rivlin KA, Ting A, Schoon RA, Abraham RT, Leibson PJ. Cytokine-enhanced NK cell-mediated cytotoxicity: positive modulatory effects of IL-2 and IL-12 on stimulus-dependent granule exocytosis. J Immunol. 1994;152(5):2098–104.PubMedGoogle Scholar
  7. Bozeman EN, He S, Shafizadeh Y, Selvaraj P. Therapeutic efficacy of PD-L1 blockade in a breast cancer model is enhanced by cellular vaccines expressing B7-1 and glycolipid-anchored IL-2. Hum Vaccines Immunother. 2016;2(2):421–30.Google Scholar
  8. Brunda MJ, Luistro L, Warrier RR, Wright RB, Hubbard BR, Murphy M, Wolf SF, Gately MK. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med. 1993;178(4):1223–30.CrossRefPubMedGoogle Scholar
  9. Carra G, Gerosa F, Trinchieri G. Biosynthesis and posttranslational regulation of human IL-12. J Immunol. 2000;164(9):4752–61.CrossRefPubMedGoogle Scholar
  10. Cesano A, Visonneau S, Clark SC, Santoli DA. Cellular and molecular mechanisms of activation of MHC nonrestricted cytotoxic cells by IL-12. J Immunol. 1993;151(6):2943–57.PubMedGoogle Scholar
  11. Chan S, Perussia B, Gupta J, Kobayashi M, Pospísil M, Young H, Trinchieri G. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991;173(4):869–79.CrossRefPubMedGoogle Scholar
  12. Chan S, 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. 1992;148(1):92–8.PubMedGoogle Scholar
  13. Chua A, Chizzonite R, Levine J, et al. Expression cloning of a human IL-12 receptor component: a new member of the cytokine receptor superfamily with strong homology to gp130. J Immunol. 1994;153(1):128–36.PubMedGoogle Scholar
  14. Cohen J. IL-12 deaths: explanation and a puzzle. Science. 1995;270:908.CrossRefPubMedGoogle Scholar
  15. Daud AI, DeConti RC, Andrews S, et al. Phase I trial of interleukin-12 plasmid electroporation in patients with meta- static melanoma. J Clin Oncol. 2008;26:5896–903.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Desai B, Quinn P, Wolitzky A, Mongini P, Chizzonite R, Gately M. IL-12 receptor. II. Distribution and regulation of receptor expression. J Immunol. 1992;148(10):3125–32.PubMedGoogle Scholar
  17. Ebert EC. Interleukin-12 up-regulates perforin- and Fas-mediated lymphokine-activated killer activity by intestinal intraepithelial lymphocytes. Clin Exp Immunol. 2004;138:259–65.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Frucht D, Fukao T, Bogdan C, Schindler H, O’Shea J, Koyasu S. IFN-gamma production by antigen-presenting cells: mechanisms emerge. Trends Immunol. 2001;22(10):556–60.CrossRefPubMedGoogle Scholar
  19. Fukao T, Matsuda S, Koyasu S. Synergistic effects of IL-4 and IL-18 on IL-12-dependent IFN-gamma production by dendritic cells. J Immunol. 2000;164(1):64–71.CrossRefPubMedGoogle Scholar
  20. Galvan DL, O’Neil RT, Foster AE, Huye L, Bear A, Rooney CM, Wilson MH. Anti-tumor effects after adoptive transfer of IL-12 transposon-modified murine splenocytes in the OT-1-melanoma mouse model. PLoS One. 2015;10(10):e0140744. doi:10.1371/journal.pone.0140744.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Gately M, Chizzonite R, Presky D. Measurement of human and mouse interleukin-12. In: Coligan John E.… et al., editors. Current protocols in immunology [serial online]. May 2001; Chapter 6:6.16.Google Scholar
  22. Gautier G, Humbert M, Hiscott J, et al. A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells. J Exp Med. 2005;201(9):1435–46.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Gollob J, Schnipper C, Murphy E, Ritz J, Frank D. The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation. J Immunol. 1999;162(8):4472–81.PubMedGoogle Scholar
  24. Grohmann U, Belladonna M, Puccetti P, et al. IL-12 acts directly on DC to promote nuclear localization of NF-kappaB and primes DC for IL-12 production. Immunity. 1998;9(3):315–23.CrossRefPubMedGoogle Scholar
  25. Grohmann U, Belladonna M, Puccetti P, et al. Positive regulatory role of IL-12 in macrophages and modulation by IFN-gamma. J Immunol. 2001;167(1):221–7.CrossRefPubMedGoogle Scholar
  26. Haicheur N, Escudier B, Dorval T, et al. Cytokines and soluble cytokine receptor induction after IL-12 administration in cancer patients. Clin Exp Immunol. 2000;119:28–37.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Heinzerling L, Burg G, Dummer R, et al. Intratumoral injection of DNA encoding human interleukin 12 into patients with metastatic melanoma: clinical efficacy. Hum Gene Ther. 2005;16:35–48.CrossRefPubMedGoogle Scholar
  28. Hsieh C, Tripp C, Murphy K, Macatonia S, O’Garra A, Wolf S. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993;260(5107):547–8.CrossRefPubMedGoogle Scholar
  29. Huang C, Ramakrishnan R, Trkulja M, Ren X, Gabrilovich DI. Therapeutic effect of intratumoral administration of DCs with conditional expression of combination of different cytokines. Cancer Immunol Immunother. 2012;61(4):573–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Hwang KS, Cho WK, Yoo J, Yun HJ, Kim S, Im DS. Adenovirus-mediated interleukin-12 gene transfer combined with cytosine deaminase followed by 5-fluorocytosine treatment exerts potent antitumor activity in Renca tumor-bearing mice. BMC Cancer. 2005;5:51.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kaufman HL, Flanagan K, Lee CS, Perretta DJ, Horig H. Insertion of interleukin-2 (IL-2) and interleukin-12 (IL-12) genes into vaccinia virus results in effective anti-tumor responses without toxicity. Vaccine. 2002;20(13–14):1862–9.CrossRefPubMedGoogle Scholar
  32. Kawamura T, Kawamura H, Van Kaer L, et al. Cutting edge: critical role of NK1 T cells in IL-12-induced immune responses in vivo. J Immunol. 1998;160(1):16–9.PubMedGoogle Scholar
  33. Kobayashi M, Fitz L, Trinchieri G, et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989;170(3):827–45.CrossRefPubMedGoogle Scholar
  34. Kramer MG, Masner M, Casales E, Moreno M, Smerdou C, Chabalgoity JA. Neoadjuvant administration of Semliki Forest virus expressing interleukin-12 combined with attenuated Salmonella eradicates breast cancer metastasis and achieves long-term survival in immunocompetent mice. BMC Cancer. 2015;15:620. doi:10.1186/s12885-015-1618-x.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Kubin M, Trinchieri G, Kamoun M. Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. J Exp Med. 1994;180(1):211–22.CrossRefPubMedGoogle Scholar
  36. Lamont AG, Adorini L. IL-12: a key cytokine in immune regulation. Immunol Today. 1996;17:214–7.CrossRefPubMedGoogle Scholar
  37. Lenzi R, Edwards R, June C, Seiden MV, Garcia ME, Rosenblum M, Freedman RS. Phase II study of intraperitoneal recombinant interleukin-12 (rhIL-12) in patients with peritoneal carcinomatosis (residual disease <1 cm) associated with ovarian cancer or primary peritoneal carcinoma. J Transl Med. 2007;5:66.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Leonard JP, Sherman ML, Fisher GL, et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood. 1997;90:2541–8.PubMedGoogle Scholar
  39. Li X, Zhang P, Liu X, Lv P. Expression of interleukin-12 by adipose-derived mesenchymal stem cells for treatment of lung adenocarcinoma. Thorac Cancer. 2015;6(1):80–4.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Linette GP, Hamid O, Whitman ED, et al. A phase I open- label study of Ad-RTS-hIL-12, an adenoviral vector engineered to express hIL-12 under the control of an oral activator ligand, in subjects with unrespectable stage III/Iv melanoma. J Clin Oncol. 31(15) suppl., 2013; ASCO Annual Meeting Abstracts, abstr. No. 3022.Google Scholar
  41. Little RF, Aleman K, Kumar P, et al. Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma. Blood. 2007;110:4165–71.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Macatonia S, Hosken N, Litton M, Vieira P, Hsieh C, Culpepper J, O'Garra A. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol. 1995;154(10):5071–9.PubMedGoogle Scholar
  43. Mahvi DM, Henry MB, Albertini MR, et al. Intratumoral injection of IL-12 plasmid DNA – results of a phase I/IB clinical trial. Cancer Gene Ther. 2007;14:717–23.CrossRefPubMedGoogle Scholar
  44. Manetti RR, Parronchi PP, Giudizi MG, Piccinni MP, Maggi EE, Trinchieri GG, Romagnani SS. 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. 1993;177(4):1199–204.CrossRefPubMedGoogle Scholar
  45. Micallef M, Ohtsuki T, Kohno K, Tanabe F, Ushio S, Namba M, Kurimoto M. Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production. Eur J Immunol. 1996;26(7):1647–51.CrossRefPubMedGoogle Scholar
  46. Munder M, Mallo M, Eichmann K, Modolell M. Murine macrophages secrete interferon γ upon combined stimulation with interleukin (IL)-12 and IL-18: a novel pathway of autocrine macrophage activation. J Exp Med. 1998;187(12):2103–8.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Portielje JE, Kruit WH, Schuler M, et al. Phase I study of subcutaneously administered recombinant human interleukin 12 in patients with advanced renal cell cancer. Clin Cancer Res. 1999;5:3983–9.PubMedGoogle Scholar
  48. Presky D, Yang H, Gubler U, et al. A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proc Natl Acad Sci U S A. 1996;93(24):14002–7.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Ren G, Tian G, Liu Y, et al. Recombinant Newcastle Disease virus encoding IL-12 and/or IL-2 as potential candidate for hepatoma carcinoma therapy. Technol Cancer Res Treat. 2015; Aug 24.pii:1533034615601521.Google Scholar
  50. Rook AH, Wood GS, Yoo EK, et al. Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Blood. 1999;94:902–8.PubMedGoogle Scholar
  51. Rubinstein MP, Su EW, Suriano S, et al. Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8(+) T cells. Cancer Immunol Immunother. 2015;64(5):539–49.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Rudman SM, Jameson MB, McKeage MJ, et al. A phase 1 study of AS1409, a novel antibody-cytokine fusion protein, in patients with malignant melanoma or renal cell carcinoma. Clin Cancer Res. 2011;17:1998–2005.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Schindler H, Lutz M, Röllinghoff M, Bogdan C. The production of IFN-gamma by IL-12/IL-18-activated macrophages requires STAT4 signaling and is inhibited by IL-4. J Immunol. 2001;166(5):3075–82.CrossRefPubMedGoogle Scholar
  54. Sinigaglia F, D'Ambrosio D, Panina-Bordignon P, Rogge L. Regulation of the IL-12 / IL-12R axis: a critical step in T-helper cell differentiation and effector function. Immunol Rev. 1999;170(1):65–72.CrossRefPubMedGoogle Scholar
  55. Stern A, Podlaski F, Gately M, et al. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A. 1990;87:6808.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Stober D, Schirmbeck R, Reimann J. IL-12/IL-18-dependent IFN-gamma release by murine dendritic cells. J Immunol. 2001;167(2):957–65.CrossRefPubMedGoogle Scholar
  57. Taoufik Y, Durali DD, De Goër De Herve MG, Giron-Michel JJ, Azzarone BB, Delfraissy JF. In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment. Blood. 2003;102(12):4084–9.CrossRefPubMedGoogle Scholar
  58. Thierfelder W, Van Deursen J, Ihle J, et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature. 1996;382(6587):171–4.CrossRefPubMedGoogle Scholar
  59. Vignali D, Kuchroo V. IL-12 family cytokines: immunological playmakers. Nat Immunol. 2012;13(8):722–8.CrossRefPubMedPubMedCentralGoogle Scholar
  60. Vo JL, Yang L, Kurtz SL, Smith SG, Koppolu BP, Ravindranathan S, Zaharoff DA. Neoadjuvant immunotherapy with chitosan and interleukin-12 to control breast cancer metastasis. Oncoimmunology. 2015;3(12):e968001.CrossRefPubMedPubMedCentralGoogle Scholar
  61. Vogel L, Lester T, Metzger D, Van Cleave V. Inhibition of murine B1 lymphocytes by interleukin-12. Eur J Immunol. 1996;26(1):219–23.CrossRefPubMedGoogle Scholar
  62. Wadler S, Levy D, Weller E, Frederickson H, Falkson C, Wang Y, Kadish A. A phase II trial of interleukin-12 in patients with advanced cervical cancer: clinical and immunologic correlates: Eastern Cooperative Oncology Group study E1E96. Gynecol Oncol. 2004;92(3):957–64.CrossRefPubMedGoogle Scholar
  63. Walker W, Hunter C, Aste-Amezaga M, Trinchieri G, Kastelein R. IL-18 and CD28 use distinct molecular mechanisms to enhance NK cell production of IL-12-induced IFN-γ. J Immunol. 1999;162(10):5894–901.PubMedGoogle Scholar
  64. Weiss JM, Subleski JJ, Wigginton JM, Wiltrout RH. Immunotherapy of cancer by IL-12-based cytokine combinations. Exp Opin Biol Ther. 2007;7:1705–21.CrossRefGoogle Scholar
  65. Xing Z, Zganiacz A, Santosuosso M. Role of IL-12 in macrophage activation during intracellular infection: IL-12 and mycobacteria synergistically release TNF-α and nitric oxide from macrophages via IFN-γ induction. J Leukoc Biol. 2000;68(6):897–902.PubMedGoogle Scholar
  66. Ye J, Ortaldo J, Conlon K, Winkler-Pickett R, Young H. Cellular and molecular mechanisms of IFN-gamma production induced by IL-2 and IL-12 in a human NK cell line. J Leukoc Biol. 1995;58(2):225–33.PubMedGoogle Scholar
  67. Yoshimoto T, Okamura H, Tagawa Y, Iwakura Y, Nakanishi K. Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-γ production from activated B cells. Proc Natl Acad Sci U S A. 1997;94(8):3948–53.CrossRefPubMedPubMedCentralGoogle Scholar
  68. Yoshimoto T, Ohkusu K, Nakanishi K, Kashiwamura S, Okamura H, Takeda K, Akira S. IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-γ production. J Immunol. 1998;161(7):3400–7.PubMedGoogle Scholar
  69. Younes A, Pro B, Robertson MJ, et al. Phase II clinical trial of interleukin-12 in patients with relapsed and refractory non-Hodgkin’s lymphoma and Hodgkin’s disease. Clin Cancer Res. 2004;10:5432–8.CrossRefPubMedGoogle Scholar
  70. Zhang L, Morgan RA, Beane JD, et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin Cancer Res. 2015;21(10):2278–88.CrossRefPubMedPubMedCentralGoogle Scholar
  71. Zola H. High-sensitivity immunofluorescence/flow cytometry: detection of cytokine receptors and other low-abundance membrane molecules. Current protocols in cytometry/editorial board, J. Paul Robinson, Managing Editor … [Et Al.] [serial online]. November 1, 2004; Chapter 6: Unit 6.3.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Division of Surgical Oncology, Rutgers Robert Wood Johnson Medical SchoolRutgers Cancer Institute of New JerseyNew BrunswickUSA

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