Skip to main content
SpringerLink
Log in

Interleukin-12

Immunologic and Antitumor Effects in Human Malignant Melanoma

  • Chapter
Melanoma

Part of the book series: Current Clinical Oncology ((CCO))

  • 124 Accesses

Abstract

Interleukin-12 (IL-12) is a pleotrophic cytokine originally referred to as a natural killer (NK) cell stimulatory factor or a cytotoxic lymphocyte maturation factor (1,2). It was identified as a factor secreted by Epstein Barr virus-transformed B cell lines. Its production can be induced by bacteria, intracellular parasites, viruses, or their products in T cell-dependent and -independent pathways. IL-12 has proinflammatory and immunoregulatory activities, with major effects on T and NK cells. It is an inducer of a type 1 (Th-1) immune response and appears to have critical roles in resistance to both infections and tumors (3–5). These observations stimulated clinical trials with this cytokine in patients with viral infections, e.g., hepatitis, and with neoplasms such as malignant melanoma.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 54.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Kobayashi M, Fitz L, Ryan 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 1989; 170: 827–845.

    Article  PubMed  CAS  Google Scholar 

  2. Gately MK, Wilson DE, Wong HL. Synergy between recombinant interleukin 2 (rIL 2) and IL 2-depleted lymphokine-containing supernatants in facilitating allogeneic human cytolytic T lymphocyte responses in vitro. J Immunol 1986; 136: 1274–1282.

    PubMed  CAS  Google Scholar 

  3. Gately MK, Wolitzky AG, Quinn PM, Chizzonite R. Regulation of human cytolytic lymphocyte responses by interleukin-12. Cell Immunol 1992; 143: 127–142.

    Article  PubMed  CAS  Google Scholar 

  4. Gately MK, Desai BB, Wolitzky AG, et al. Regulation of human lymphocyte proliferation by a heterodimeric cytokine IL-12 (cytotoxic lymphocyte maturation factor). J Immunol 1992; 147: 874–882.

    Google Scholar 

  5. Chan SH, Perussai B, Gupta JW, et al. 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: 869–879.

    Article  PubMed  CAS  Google Scholar 

  6. Podlaski FJ, Nanduri VB, Hulmes JD, et al. Molecular characterization of interleukin 12. Arch Biochem Biophys 1992; 294: 230–237.

    Article  PubMed  CAS  Google Scholar 

  7. Stern AS, Podlaski FJ, Hulmes JD, et al. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci USA 1990; 87: 6808–6812.

    Article  PubMed  CAS  Google Scholar 

  8. Wolf SF, Temple PA, Kobayashi M, 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 1991; 146: 3074–3081.

    PubMed  CAS  Google Scholar 

  9. Gubler U, Chua AO, Schoenhaut DS, et al. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci USA 1991; 88: 4143–4147.

    Article  PubMed  CAS  Google Scholar 

  10. Schoenhaut DS, Chua AO, Wolitzky AG, et al. Cloning and expression of murine IL-12. J Immunol 1992; 148: 3433–3440.

    PubMed  CAS  Google Scholar 

  11. Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type I and cytotoxic lymphocytes. Blood 1994; 84: 4008–4027.

    PubMed  CAS  Google Scholar 

  12. Murphy EE, Terres G, Macatonia SE, et al. B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation. J Exp Med 1994; 180: 223–231.

    Article  PubMed  CAS  Google Scholar 

  13. Mergerg DM, Wolf SF, Clark SC. Sequence similarity between NKSF and the IL-6/G-CSF family (letter). Immunol Today 1992; 13: 77–78.

    Article  Google Scholar 

  14. Gearing DP, Cosman D. Homology of the p40 subunit of natural killer cell stimulatory factor (NKSF) with the extracellular domain of the interleukin-6 receptor (letter). Cell 1991; 66: 9–10.

    Article  PubMed  CAS  Google Scholar 

  15. Sieburth D, Jabs EW, Warrington JA, et al. Assignment of genes encoding a unique cytokine (IL 12) composed of two unrelated subunits to chromosomes 3 and 5. Genomics 1992; 14: 59–62.

    Article  PubMed  CAS  Google Scholar 

  16. D’Andrea A, Rengaraju M, Valiante NM, et al. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med 1992; 176: 1387 1398.

    Google Scholar 

  17. Macatonia SE, Hsieh CS, Murphy KM, O’Garra A. Dendritic cells and macrophages are required for Thl development of CD4+ T cells from alpha beta TCR transgenic mice: IL-12 substitution for macrophages to stimulate IFN-gamma production is FIN-gamma-dependent. Intlmmunol 1993; 5: 1119–1128.

    CAS  Google Scholar 

  18. Curtsinger JM, Schmidt CS, Mondino A, et al. Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ cells. J Immunol 1991; 162: 3256–3262.

    Google Scholar 

  19. Hall SS. IL-12 at the crossroads (news) [see comments]. Science 1995; 268: 1432–1434.

    Article  PubMed  CAS  Google Scholar 

  20. Guery JC, Ria F, Galgiati F, Adorini L. Normal B cells fail to secrete interleukin-12. Eur J Immunol 1997; 27: 1632–1639.

    Article  PubMed  CAS  Google Scholar 

  21. Macatonia SE, Hosken NA, Litton M, et al. Dendritic cells produce IL-12 and direct the development of Thl cells from naive CD4+ T cells. J Immunol 1995; 154: 5071–5079.

    PubMed  CAS  Google Scholar 

  22. Cassatella MA, Meda L, Gasperini S, D’Andrea A, Ma X, Trinchieri G. Interleukin-l2 production by human polymorphonuclear leukocytes. Eur J Immunol 1995; 25: 1–5.

    Article  PubMed  CAS  Google Scholar 

  23. Kubin M, Chow JM, Trinchieri G. 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 1994; 83: 1847–1855.

    PubMed  CAS  Google Scholar 

  24. D’Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressive natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med 1993; 178: 1041–1048.

    Article  PubMed  Google Scholar 

  25. D’Andrea A, Ma X, Ate-Amezaga M, Paganin C, Tinchieri 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 alpha production. J Exp Med 1995; 181: 537–546.

    Article  PubMed  Google Scholar 

  26. Shu U, Kiniwa M, Wu CY, et al. Activated T cells induce interleukin-12 production by monocytes via CD40–CD40ligand interaction. Eur J Immunol 1995; 25: 1125–1128.

    Article  PubMed  CAS  Google Scholar 

  27. Hunter CA, Ellis-Neyer L, Gabriel KE, et al. The role of the CD28/B7 interaction in the regulation of NK cell responses during infection with Toxoplasma gondii. J Immunol 1997; 158: 2285–2293.

    PubMed  CAS  Google Scholar 

  28. McDyer JF, Goletz TJ, Thomas E, June CH, Seder RA. CD40 ligand/CD40 stimulation regulates the production of IFN-gamma from human peripheral blood mononuclear cells in an IL-12- and/or CD27-dependent manner. J Immunol 1998; 160: 1701–1707.

    PubMed  CAS  Google Scholar 

  29. Gollob JA, Schnipper CP, Orsini E, et al. Characterization of a novel subset of CD8(+) T cells that expands in patients receiving interleukin-12. J Clin Invest 1998; 102: 561–575.

    Article  PubMed  CAS  Google Scholar 

  30. Gately MK, Renzetti LM, MagramJ, et al. The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol 1998; 16: 495–521.

    Article  PubMed  CAS  Google Scholar 

  31. Adorini L. Interleukin-12, a key cytokine in Thl-mediated autoimmune diseases. Cell Mol Life Sci 1999; 55: 1610–1625.

    Article  PubMed  CAS  Google Scholar 

  32. 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 1998; 160: 5936–5940.

    PubMed  CAS  Google Scholar 

  33. Mosmann TR, Coffman RL. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol 1989; 46: 111–147.

    Article  PubMed  CAS  Google Scholar 

  34. Mosmann TR, Coffman RL. Thl and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989; 7: 145–173.

    Article  PubMed  CAS  Google Scholar 

  35. Thibodeaux DK, Hunter SE, Waldburger KE, et al. Autocrine regulation of IL-12 receptor expression is independent of secondary IFN-gamma secretion and not restricted to T and Nic cells. J Immunol 1999; 163: 5257–5264.

    PubMed  CAS  Google Scholar 

  36. Showe LC, Fox FE, Williams D, Au K, Niu Z, Rook AH. Depressed IL-12-mediated signal transduction in T cells from patients with Sézary syndrome is associated with the absence of IL-12 receptor beta 2 mRNA and high reduced levels of STAT4. J Immunol 1999; 163: 40734079.

    Google Scholar 

  37. Wang X, Wilkinson VL, Podlaski FJ, et al. Characterization of mouse interleukin-12 p40 homodimer binding to the interleukin-12 rector subunits. Eur Jlmmunol 1999; 29: 2007–2013.

    Article  CAS  Google Scholar 

  38. Murphy KM, Ouyang W, Szabo SJ, et al. T helper differentiation proceeds through Statldependent, Stat4-dependent and Stat4-independent phases. Curr Top Microbiol Immunol 1999; 238: 13–26.

    PubMed  CAS  Google Scholar 

  39. Naeger LK, McKinney J, Salvekar A, Hoey T. Identification of a STAT4 binding site in the interleukin-12 receptor required for signaling. J Biol Chem 1999; 273: 1875–1878.

    Article  Google Scholar 

  40. Rogge L, Papi A, Presky DH, et al. Antibodies to the IL-12 receptor beta 2 chain mark human Thl but not Th2 cells in vitro and in vivo. J Immunol 1999; 162: 3926–3932.

    PubMed  CAS  Google Scholar 

  41. Mountford AP, Coulson PS, Cheever AW, Sher A, Wilson RA, Wynn TA. Interleukin-12 can directly induce T-helper 1 responses in interferon-gamma (IFN-gamma) receptor-deficient mice, but requires IFN-gamma signaling to downregulate T-helper 2 responses. Immunology 1999; 97: 588–594.

    Article  PubMed  CAS  Google Scholar 

  42. Zhang F, Nakamura T, Aune TM. TCR and IL-12 receptor signals cooperative to activate an individual response element in the IFN-gamma promoter in effector Th cells. J Immunol 1999; 163: 728–735.

    PubMed  CAS  Google Scholar 

  43. Yamamoto K, Shibata F, Miura O, Kamiyama R, Hirosawa S, Miyasaka N. Physical interaction between interleukin-12 receptor beta 2 subunit and Jak2 tyrosine kinase: Jak2 associates with cytoplasmic membrane-proximal region of interleukin-12 and receptor beta 2 via aminoterminus. Biochem Biophys Res Commun 1999: 275: 400–404.

    Article  Google Scholar 

  44. Yao BB, Niu P, Surowy CS, Faltynek CR. Direct interaction of STAT4 with the IL-12 receptor. Arch Biochem Biophys 1999; 368: 147: 155.

    Google Scholar 

  45. Akira S. Functional roles of STAT family proteins: lessons from knockout mice. Stem Cells 1999; 17: 138–146.

    Article  PubMed  CAS  Google Scholar 

  46. Ouyang W. Jacobson NG, Bhattacharya D, et al. The Ets transcription factor ERM is Thlspecific and induced by IL-12 through a Stat4-dependent pathway. Proc Natl Acad Sci USA 1999; 96: 3888–3893.

    Article  PubMed  Google Scholar 

  47. Brunda MJ, Luistro L, Warner RR, et al. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med 1993; 178: 1223–1230.

    Article  PubMed  CAS  Google Scholar 

  48. Tannenbaum CS, Tubbs R, Armstrong D, Finke JH, Bukowski RM, Hamilton TA. The CXC chemokines IP-10 and Mig are necessary for IL-12-mediated regression of the mouse RENCA tumor. J Immunol 1998; 161: 927–932.

    PubMed  CAS  Google Scholar 

  49. Nastala CL, Edington HD, McKinney TG, et al. Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. Jlmmunol 1994; 153: 1697–1706.

    CAS  Google Scholar 

  50. Gately MK, Gubler U, Brunda MJ, et al. Interleukin-12: a cytokine with therapeutic potential in oncology and infectious diseases. Ther Immunol 1994; 1: 187–196.

    PubMed  CAS  Google Scholar 

  51. Mu Z, Zou JP, Yamamoto N, et al. Administration of recombinant interleukin 12 prevents outgrowth of tumor cells metastasizing spontaneously to lung and lymph nodes. Cancer Res 1995; 55: 4404 4408.

    Google Scholar 

  52. Dias S, Thomas H, Balkwill F. Multiple molecular and cellular changes associated with tumour static and regression during IL-12 therapy of a murine breast cancer model. Int J Cancer 1998; 75: 151–157.

    Article  PubMed  CAS  Google Scholar 

  53. Brunda MJ, Luistro L, Rumennik L, et al. Antitumor activity of interleukin 12 in preclinical models. Cancer Chemother Pharmacol 1996; 38 (Suppl): S16 - S21.

    Article  Google Scholar 

  54. Brunda MJ, Luistro L, Hendrzak JA, Fountoulakis M, Garotta G, Gately MK. Role of interferon-gamma in mediating the antitumor efficacy of interleukin-12. J Immunother Emphasis Tumor Immunol 1995; 17: 71–77.

    Article  PubMed  CAS  Google Scholar 

  55. Colombo MP, Vagliani M. Spreafico F, et al. Amount of interleukin 12 available at the tumor site is critical for tumor regression. Cancer Res 1996; 56: 2531–2534.

    PubMed  CAS  Google Scholar 

  56. Tannenbaum CS, Wicker N, Armstrong D, et al. Cytokine and chemokine expression in tumors of mice receiving systemic therapy with IL-12. J Immunol 1996; 156: 693–699.

    PubMed  CAS  Google Scholar 

  57. Bukowski RM, Rayman P, Molto L, et al. Interferon-gamma and CXC chemokine induction by interleukin 12 in renal cell carcinoma Clin Cancer Res 1999; 5; 2780–2789.

    PubMed  CAS  Google Scholar 

  58. Ha SJ, Lee SB, Kim CM, Shin HS, Sung YC. Rapid recruitment of macrophages in interleukin12 mediated tumour regression. Immunology 1998; 95: 156–153.

    Article  PubMed  CAS  Google Scholar 

  59. Hashimoto W, Osaki T, Okamura H, et al. Differential antitumor effects of administration of recombinant IL-18 or recombinant IL-12 are mediated primarily by Fas-Fas ligand and perforin-induced tumor apoptosis, respectively. J Immunol 1999; 163: 583–589.

    PubMed  CAS  Google Scholar 

  60. Cavallo F, Di Carolo E, Butera M, et al. Immune events associated with the cure of established tumors and spontaneous metastases by local and systemic interleukin 12. Cancer Res 1999; 59: 414–421.

    PubMed  CAS  Google Scholar 

  61. Wiggington JM, Kuhns DB, Back TC, Brunda MJ, Wiltroug RH, Cox GW. Interleukin 12 primes macrophages for nitric oxide production in vivo and restores depressed nitric oxide production by macrophages from tumor-bearing mice: implications for the antitumor activity of interleukin 12 and/or interleukin 2. Cancer Res 1996; 56: 1131–1136.

    Google Scholar 

  62. Angiolillo AL, Sgadari C, Tosato G. A role for interferon-inducible protein 10 in inhibition of angiogenesis by interleukin-12. Ann NYAcad Sci 1996; 795: 158–167.

    Article  PubMed  CAS  Google Scholar 

  63. Kerbel RS, Hawley RG. Interleukin 12: newest member of the antiangiogenesis club [editorial; comment]. J Natl Cancer Inst 1995; 87: 557–559.

    Article  PubMed  CAS  Google Scholar 

  64. Sgadari C, Angiolillo AL, Tosato G. Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood 1996; 87: 3877–3882.

    PubMed  CAS  Google Scholar 

  65. O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88: 277–285.

    Article  PubMed  Google Scholar 

  66. Voest EE, Kenyon BM, O’Reilly MS, Truitt G, D’ Amato RJ, Folkman J. Inhibition of angiogenesis in vivo by interleukin 12 [see comments]. J Natl Cancer Inst 1995; 87: 581–586.

    Article  PubMed  CAS  Google Scholar 

  67. Strieter RM, Kunkel SL, Arenberg DA, Burdick MD, Polverini PJ. Interferon gamma-inducible protein 10 (IP-10), a member of the C-X-C chemokine family, is an inhibitor of angiogenesis. Biochem Biophys Res Commun 1995; 210: 51–57.

    Article  PubMed  CAS  Google Scholar 

  68. Luster AD, Greenberg SM, Leder P. The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. J Exp Med 1995; 182: 219–231.

    Article  PubMed  CAS  Google Scholar 

  69. Sgadari C, Farber JM, Angiolillo AL, et al. Mig, the monokine induced by interferon-gamma, promotes tumor necrosis in vivo. Blood 1997; 89: 2635–2643.

    PubMed  CAS  Google Scholar 

  70. Kanegane C, Sgadari C, Kanagane H, et al. Contribution of the CXC chemokines IP-10 and Mig to the antitumor effects of IL-12. J Leukoc Biol 1998; 64: 384–392.

    PubMed  CAS  Google Scholar 

  71. Motzer RJ, Rakhit A, Schwartz LH, et al. Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma. Clin Cancer Res 1998; 4: 1183 1191.

    Google Scholar 

  72. 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: 409–417.

    PubMed  CAS  Google Scholar 

  73. Mier J, Dollob JA, Atkins M. Interleukin 12, a new antitumor cytokine. Int J Immunopath Pharm 1998; 11: 109–115.

    CAS  Google Scholar 

  74. Rakhit A, Yeon MM, Ferrante J, et al. Down-regulation of the pharmacokinetic-pharmacodynamic response to interleukin-12 during long-term administration to patients with renal cell carcinoma and evaluation of the mechanism of this “adaptive response” in mice. Clin Pharmacol Ther 1999; 65: 615–629.

    Article  PubMed  CAS  Google Scholar 

  75. Bajetta E, Del Vecchio M, Mortarini R, et al. Pilot study of subcutaneous recombinant human interleukin 12 in metastatic melanoma. Clin Cancer Res 1998; 4: 75–85.

    PubMed  CAS  Google Scholar 

  76. Robertson MJ, Camerin C, Atkins MB, et al. Immunological effects of interleukin 12 administered by bolus intravenous injection to patients with cancer. Clin Cancer Res 1999; 5: 9–16.

    PubMed  CAS  Google Scholar 

  77. Arenberg DA, Kunkel SL, Polverini PI, et al. Interferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases. J Exp Med 1996; 184: 981–992.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Ronald M. Bukowski MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles Tannenbaum PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Center for Cancer Drug Discovery and Development, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH, USA

    Ernest C. Borden MD (Director) (Director)

Rights and permissions

Reprints and permissions

Copyright information

© 2002 Humana Press Inc.,Totowa, NJ

About this chapter

Cite this chapter

Bukowski, R.M., Tannenbaum, C. (2002). Interleukin-12. In: Borden, E.C. (eds) Melanoma. Current Clinical Oncology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-159-6_8

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-159-6_8

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4684-9668-0

  • Online ISBN: 978-1-59259-159-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation