Emerging Roles for Interleukin-18 in the Gastrointestinal Tumor Microenvironment

  • Ka Yee Fung
  • Paul M. Nguyen
  • Tracy L. PutoczkiEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1240)


Interleukin (IL)-18, a member of the IL-1 family of cytokines, has emerged as a key regulator of mucosal homeostasis within the gastrointestinal tract. Like other members of this family, IL-18 is secreted as an inactive protein and is processed into its active form by caspase-1, although other contributors to precursor processing are emerging.

Numerous studies have evaluated the role of IL-18 within the gastrointestinal tract using genetic or complementary pharmacological tools and have revealed multiple roles in tumorigenesis. Most striking among these are the divergent roles for IL-18 in colon and gastric cancers. Here, we review our current understanding of IL-18 biology and how this applies to colorectal and gastric cancers.


Cancer Colon Caspase-1 Cytokines Gastric Inflammation IL-1 IL-12 IL-18 IL-18BP IFNγ, Gastrointestinal Microenvironment NfkB Therapeutics 



The Walter and Eliza Hall Institute receives funding from the Victorian State Government Operational Infrastructure Support Program. TLP receives funding from the National Health and Medical Research Council (NHMRC) of Australia Project Grants (1080498, 1098643). TLP is a Victorian Cancer Agency Fellow and WEHI Dyson Bequest Centenary Fellow.

Conflict of Interest

The authors declare no conflicts.


  1. 1.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. Scholar
  2. 2.
    Nguyen PM, Putoczki TL (2018) Could the inhibition of IL-17 or IL-18 be a potential therapeutic opportunity for gastric cancer? Cytokine 118:8. Scholar
  3. 3.
    Garlanda C, Dinarello CA, Mantovani A (2013) The interleukin-1 family: back to the future. Immunity 39:1003–1018. Scholar
  4. 4.
    Nakamura K, Okamura H, Wada M, Nagata K, Tamura T (1989) Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun 57:590–595CrossRefGoogle Scholar
  5. 5.
    Okamura H et al (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378:88–91. Scholar
  6. 6.
    Kato Z et al (2003) The structure and binding mode of interleukin-18. Nat Struct Biol 10:966–971. Scholar
  7. 7.
    Ushio S et al (1996) Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J Immunol 156:4274–4279PubMedGoogle Scholar
  8. 8.
    Ghayur T et al (1997) Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature 386:619–623. Scholar
  9. 9.
    Yamanaka K et al (2000) Skin-specific caspase-1-transgenic mice show cutaneous apoptosis and pre-endotoxin shock condition with a high serum level of IL-18. J Immunol 165:997–1003. Scholar
  10. 10.
    Sugawara S et al (2001) Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells. J Immunol 167:6568–6575. Scholar
  11. 11.
    Tsutsui H et al (1999) Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice. Immunity 11:359–367CrossRefGoogle Scholar
  12. 12.
    Bossaller L et al (2012) Cutting edge: FAS (CD95) mediates noncanonical IL-1beta and IL-18 maturation via caspase-8 in an RIP3-independent manner. J Immunol 189:5508–5512. Scholar
  13. 13.
    Kim KE et al (2009) Expression of ADAM33 is a novel regulatory mechanism in IL-18-secreted process in gastric cancer. J Immunol 182:3548–3555. Scholar
  14. 14.
    Dinarello CA, Novick D, Kim S, Kaplanski G (2013) Interleukin-18 and IL-18 binding protein. Front Immunol 4:289. Scholar
  15. 15.
    Munoz M et al (2015) Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity 42:321–331. Scholar
  16. 16.
    Nowarski R et al (2015) Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163:1444–1456. Scholar
  17. 17.
    Pizarro TT et al (1999) IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn’s disease: expression and localization in intestinal mucosal cells. J Immunol 162:6829–6835PubMedGoogle Scholar
  18. 18.
    Torigoe K et al (1997) Purification and characterization of the human interleukin-18 receptor. J Biol Chem 272:25737–25742. Scholar
  19. 19.
    Born TL, Thomassen E, Bird TA, Sims JE (1998) Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling. J Biol Chem 273:29445–29450. Scholar
  20. 20.
    Hoshino K et al (1999) Cutting edge: generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding receptor. J Immunol 162:5041–5044PubMedGoogle Scholar
  21. 21.
    Tsutsumi N et al (2014) The structural basis for receptor recognition of human interleukin-18. Nat Commun 5:5340. Scholar
  22. 22.
    Akira S (2000) The role of IL-18 in innate immunity. Curr Opin Immunol 12:59–63CrossRefGoogle Scholar
  23. 23.
    Kanai T et al (2000) Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn’s disease. Gastroenterology 119:1514–1523CrossRefGoogle Scholar
  24. 24.
    Adachi O et al (1998) Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9:143–150CrossRefGoogle Scholar
  25. 25.
    Kanakaraj P et al (1999) Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. J Exp Med 189:1129–1138. Scholar
  26. 26.
    Kojima H et al (1998) Interleukin-18 activates the IRAK-TRAF6 pathway in mouse EL-4 cells. Biochem Biophys Res Commun 244:183–186. Scholar
  27. 27.
    Lee JK et al (2004) Differences in signaling pathways by IL-1beta and IL-18. Proc Natl Acad Sci U S A 101:8815–8820. Scholar
  28. 28.
    Alboni S et al (2014) Interleukin 18 activates MAPKs and STAT3 but not NF-kappaB in hippocampal HT-22 cells. Brain Behav Immun 40:85–94. Scholar
  29. 29.
    Kalina U et al (2000) IL-18 activates STAT3 in the natural killer cell line 92, augments cytotoxic activity, and mediates IFN-gamma production by the stress kinase p38 and by the extracellular regulated kinases p44erk-1 and p42erk-21. J Immunol 165:1307–1313. Scholar
  30. 30.
    Novick D et al (1999) Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 10:127–136CrossRefGoogle Scholar
  31. 31.
    Kim SH et al (2000) Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci U S A 97:1190–1195. Scholar
  32. 32.
    Hurgin V, Novick D, Rubinstein M (2002) The promoter of IL-18 binding protein: activation by an IFN-gamma -induced complex of IFN regulatory factor 1 and CCAAT/enhancer binding protein beta. Proc Natl Acad Sci U S A 99:16957–16962. Scholar
  33. 33.
    Muhl H et al (2000) Interferon-gamma mediates gene expression of IL-18 binding protein in nonleukocytic cells. Biochem Biophys Res Commun 267:960–963. Scholar
  34. 34.
    Takeda K et al (1998) Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 8:383–390CrossRefGoogle Scholar
  35. 35.
    Robinson D et al (1997) IGIF does not drive Th1 development but synergizes with IL-12 for interferon-gamma production and activates IRAK and NFkappaB. Immunity 7:571–581CrossRefGoogle Scholar
  36. 36.
    Xu D et al (1998) Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells. J Exp Med 188:1485–1492. Scholar
  37. 37.
    Yoshimoto T et al (1998) IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J Immunol 161:3400–3407PubMedGoogle Scholar
  38. 38.
    Barbulescu K et al (1998) IL-12 and IL-18 differentially regulate the transcriptional activity of the human IFN-gamma promoter in primary CD4+ T lymphocytes. J Immunol 160:3642–3647PubMedGoogle Scholar
  39. 39.
    Tominaga K et al (2000) IL-12 synergizes with IL-18 or IL-1beta for IFN-gamma production from human T cells. Int Immunol 12:151–160. Scholar
  40. 40.
    Hyodo Y et al (1999) IL-18 up-regulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor. J Immunol 162:1662–1668PubMedGoogle Scholar
  41. 41.
    Senju H et al (2018) Effect of IL-18 on the expansion and phenotype of human natural killer cells: application to cancer immunotherapy. Int J Biol Sci 14:331–340. Scholar
  42. 42.
    Son YI et al (2001) Interleukin-18 (IL-18) synergizes with IL-2 to enhance cytotoxicity, interferon-gamma production, and expansion of natural killer cells. Cancer Res 61:884–888PubMedGoogle Scholar
  43. 43.
    Okamoto I, Kohno K, Tanimoto T, Ikegami H, Kurimoto M (1999) Development of CD8+ effector T cells is differentially regulated by IL-18 and IL-12. J Immunol 162:3202–3211PubMedGoogle Scholar
  44. 44.
    Li W, Kashiwamura S, Ueda H, Sekiyama A, Okamura H (2007) Protection of CD8+ T cells from activation-induced cell death by IL-18. J Leukoc Biol 82:142–151. Scholar
  45. 45.
    Oliveira AC et al (2017) Crucial role for T cell-intrinsic IL-18R-MyD88 signaling in cognate immune response to intracellular parasite infection. Elife 6.
  46. 46.
    Harrison OJ et al (2015) Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3(+) Treg cell function in the intestine. Mucosal Immunol 8:1226–1236. Scholar
  47. 47.
    Tye H et al (2018) NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease. Nat Commun 9:3728. Scholar
  48. 48.
    Levy M et al (2015) Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163:1428–1443. Scholar
  49. 49.
    Hand TW (2015) Interleukin-18: the bouncer at the mucosal bar. Cell 163:1310–1312. Scholar
  50. 50.
    Peluso I, Pallone F, Monteleone G (2006) Interleukin-12 and Th1 immune response in Crohn’s disease: pathogenetic relevance and therapeutic implication. World J Gastroenterol 12:5606–5610. Scholar
  51. 51.
    Kanai T et al (2001) Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn’s disease. Gastroenterology 121:875–888. Scholar
  52. 52.
    Siegmund B et al (2001) Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production. Am J Physiol Regul Integr Comp Physiol 281:R1264–R1273. Scholar
  53. 53.
    Sivakumar PV et al (2002) Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage. Gut 50:812–820. Scholar
  54. 54.
    Siegmund B, Lehr HA, Fantuzzi G, Dinarello CA (2001) IL-1 beta -converting enzyme (caspase-1) in intestinal inflammation. Proc Natl Acad Sci U S A 98:13249–13254. Scholar
  55. 55.
    Dupaul-Chicoine J et al (2010) Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32:367–378. Scholar
  56. 56.
    Zaki MH et al (2010) The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32:379–391. Scholar
  57. 57.
    Elinav E et al (2011) NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745–757. Scholar
  58. 58.
    Takagi H et al (2003) Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulphate colitis in mice. Scand J Gastroenterol 38:837–844CrossRefGoogle Scholar
  59. 59.
    Gersemann M et al (2009) Differences in goblet cell differentiation between Crohn’s disease and ulcerative colitis. Differentiation 77:84–94. Scholar
  60. 60.
    Nikiteas N, Yannopoulos A, Chatzitheofylaktou A, Tsigris C (2007) Heterozygosity for interleukin-18 -607 A/C polymorphism is associated with risk for colorectal cancer. Anticancer Res 27:3849–3853PubMedGoogle Scholar
  61. 61.
    Fung KY, Putoczki T (2018) In vivo models of inflammatory bowel disease and colitis-associated cancer. Methods Mol Biol 1725:3–13. Scholar
  62. 62.
    Malik A et al (2018) SYK-CARD9 signaling axis promotes gut fungi-mediated inflammasome activation to restrict colitis and colon cancer. Immunity 49:515–530 e515. Scholar
  63. 63.
    Dupaul-Chicoine J et al (2015) The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity 43:751–763. Scholar
  64. 64.
    Tanaka F et al (2000) Rapid generation of potent and tumor-specific cytotoxic T lymphocytes by interleukin 18 using dendritic cells and natural killer cells. Cancer Res 60:4838–4844PubMedGoogle Scholar
  65. 65.
    Gatault S et al (2015) IL-18 is involved in eosinophil-mediated tumoricidal activity against a colon carcinoma cell line by upregulating LFA-1 and ICAM-1. J Immunol 195:2483–2492. Scholar
  66. 66.
    Haghshenas MR et al (2009) IL-18 serum level and IL-18 promoter gene polymorphism in Iranian patients with gastrointestinal cancers. J Gastroenterol Hepatol 24:1119–1122. Scholar
  67. 67.
    Kang JS et al (2009) Interleukin-18 increases metastasis and immune escape of stomach cancer via the downregulation of CD70 and maintenance of CD44. Carcinogenesis 30:1987–1996. Scholar
  68. 68.
    Uhlen M et al (2015) Proteomics. Tissue-based map of the human proteome. Science 347:1260419. Scholar
  69. 69.
    Deswaerte V et al (2018) Inflammasome adaptor ASC suppresses apoptosis of gastric cancer cells by an IL18-mediated inflammation-independent mechanism. Cancer Res 78:1293–1307. Scholar
  70. 70.
    Majima T et al (2006) Exploitation of interleukin-18 by gastric cancers for their growth and evasion of host immunity. Int J Cancer 118:388–395. Scholar
  71. 71.
    Osaki T et al (1998) IFN-gamma-inducing factor/IL-18 administration mediates IFN-gamma- and IL-12-independent antitumor effects. J Immunol 160:1742–1749PubMedGoogle Scholar
  72. 72.
    Micallef MJ et al (1997) In vivo antitumor effects of murine interferon-gamma-inducing factor/interleukin-18 in mice bearing syngeneic Meth A sarcoma malignant ascites. Cancer Immunol Immunother 43:361–367CrossRefGoogle Scholar
  73. 73.
    Son YI, Dallal RM, Lotze MT (2003) Combined treatment with interleukin-18 and low-dose interleukin-2 induced regression of a murine sarcoma and memory response. J Immunother 26:234–240CrossRefGoogle Scholar
  74. 74.
    Carson WE et al (2000) Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice: critical role of natural killer cell interferon-gamma production and STAT-mediated signal transduction. Blood 96:1465–1473CrossRefGoogle Scholar
  75. 75.
    Ma Z et al (2016) Augmentation of immune checkpoint cancer immunotherapy with IL18. Clin Cancer Res 22:2969–2980. Scholar
  76. 76.
    Robertson MJ et al (2013) A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin lymphoma. J Immunother 36:331–341. Scholar
  77. 77.
    Tarhini AA et al (2009) A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma. Cancer 115:859–868. Scholar
  78. 78.
    Gabay C et al (2018) Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still’s disease. Ann Rheum Dis 77:840–847. Scholar
  79. 79.
    Mistry P et al (2014) Safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose antiinterleukin- 18 mAb GSK1070806 in healthy and obese subjects. Int J Clin Pharmacol Ther 52:867–879. Scholar
  80. 80.
    O’Reilly M et al (2014) Gene therapy: charting a future course--summary of a National Institutes of Health Workshop, April 12, 2013. Hum Gene Ther 25:488–497. Scholar
  81. 81.
    Rodriguez-Galan MC et al (2009) Coexpression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL-10 without affecting its antitumor capacity. J Immunol 183:740–748. Scholar
  82. 82.
    Higashi K et al (2014) A novel cancer vaccine strategy with combined IL-18 and HSV-TK gene therapy driven by the hTERT promoter in a murine colorectal cancer model. Int J Oncol 45:1412–1420. Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Ka Yee Fung
    • 1
  • Paul M. Nguyen
    • 1
  • Tracy L. Putoczki
    • 1
    • 2
    Email author
  1. 1.Personalized Oncology DivisionThe Walter and Eliza Hall Institute of Medical ResearchParkvilleAustralia
  2. 2.Department of Medical BiologyUniversity of MelbourneParkvilleAustralia

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