Interleukin-32: Frenemy in cancer?

Han, Sora;Yang, Young

  • Received : 2018.11.19
  • Published : 2019.03.31


Interleukin-32 (IL-32) was originally identified in natural killer (NK) cells activated by IL-2 in 1992. Thus, it was named NK cell transcript 4 (NK4) because of its unknown function at that time. The function of IL-32 has been elucidated over the last decade. IL-32 is primarily considered to be a booster of inflammatory reactions because it is induced by pro-inflammatory cytokines and stimulates the production of those cytokines and vice versa. Therefore, many studies have been devoted to studying the roles of IL-32 in inflammation-associated cancers, including gastric, colon cancer, and hepatocellular carcinoma. At the same time, roles of IL-32 have also been discovered in other cancers. Collectively, IL-32 fosters the tumor progression by nuclear $factor-{\kappa}B$ ($NF-{\kappa}B$)-mediated cytokines and metalloproteinase production, as well as stimulation of differentiation into immunosuppressive cell types in some cancer types. However, it is also able to induce tumor cell apoptosis and enhance NK and cytotoxic T cell sensitivity in other cancer types. In this review, we will address the function of each IL-32 isoform in different cancer types studied to date, and suggest further strategies to comprehensively elucidate the roles of IL-32 in a context-dependent manner.


Apoptosis;Cancer stem cell (CSC);Inflammatory cancer;Interleukin 32 (IL-32);Natural killer (NK) cell;Women's cancer


  1. Zitvogel L, Tesniere A and Kroemer G (2006) Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 6, 715-727
  2. Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960-1964
  3. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA and Coffman RL (1986) Two types of murine helper T cell clone. I. definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136, 2348-2357
  4. Sakaguchi S, Miyara M, Costantino CM and Hafler DA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10, 490-500
  5. O'Sullivan KE, Phelan JJ, O'Hanlon C, Lysaght J, O'Sullivan JN and Reynolds JV (2014) The role of inflammation in cancer of the esophagus. Expert Rev Gastroenterol Hepatol 8, 749-760
  6. Tosello-Trampont A, Surette FA, Ewald SE and Hahn YS (2017) Immunoregulatory role of NK Cells in tissue inflammation and regeneration. Front Immunol 8, 301
  7. Yadav D and Lowenfels AB (2013) The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 144, 1252-1261
  8. Freeman HJ (2008) Colorectal cancer risk in Crohn's disease. World J Gastroenterol 14, 1810-1811
  9. Warren JR (2000) Gastric pathology associated with Helicobacter pylori. Gastroenterol Clin North Am 29, 705-751
  10. Noto JM and Peek RM Jr (2012) Helicobacter pylori: an overview. Methods Mol Biol 921, 7-10
  11. Sakitani K, Hirata Y, Hayakawa Y et al (2012) Role of interleukin-32 in Helicobacter pylori-induced gastric inflammation. Infect Immun 80, 3795-3803
  12. Seo EH, Kang J, Kim KH et al (2008) Detection of expressed IL-32 in human stomach cancer using ELISA and immunostaining. J Microbiol Biotechnol 18, 1606-1612
  13. Khawar MB, Abbasi MH and Sheikh N (2016) IL-32: A Novel Pluripotent inflammatory interleukin, towards gastric inflammation, gastric cancer, and chronic rhino sinusitis. Mediators Inflamm 2016, 8413768
  14. Yan H, He D, Huang X et al (2018) Role of interleukin-32 in cancer biology. Oncol Lett 16, 41-47
  15. Heinhuis B, Koenders MI, van de Loo FA, Netea MG, van den Berg WB and Joosten LA (2011) Inflammationdependent secretion and splicing of IL-$32{\gamma}$ in rheumatoid arthritis. Proc Natl Acad Sci U S A 108, 4962-4967
  16. Heinhuis B, Plantinga TS, Semango G et al (2016) Alternatively spliced isoforms of IL-32 differentially influence cell death pathways in cancer cell lines. Carcinogenesis 37, 197-205
  17. Sloot YJE SJ, Joosten LAB, Netea-Maier RT (2018) Insights into the role of IL-32 in cancer. Semin Immunol 38, 24-32
  18. Wang S, Chen F and Tang L (2015) IL-32 promotes breast cancer cell growth and invasiveness. Oncol Lett 9, 305-307
  19. Taguchi A, Ohmiya N, Shirai K et al (2005) Interleukin-8 promoter polymorphism increases the risk of atrophic gastritis and gastric cancer in Japan. Cancer Epidemiol Biomarkers Prev 14, 2487-2493
  20. Wang YM, Li ZX, Tang FB et al (2016) Association of genetic polymorphisms of interleukins with gastric cancer and precancerous gastric lesions in a high-risk Chinese population. Tumour Biol 37, 2233-2242
  21. Tsai CY, Wang CS, Tsai MM et al (2014) Interleukin-32 increases human gastric cancer cell invasion associated with tumor progression and metastasis. Clin Cancer Res 20, 2276-2288
  22. Ishigami S, Arigami T, Uchikado Y et al (2013) IL-32 expression is an independent prognostic marker for gastric cancer. Med Oncol 30, 472
  23. Erturk K, Tastekin D, Serilmez M, Bilgin E, Bozbey HU and Vatansever S (2006) Clinical significance of serum interleukin-29, interleukin-32, and tumor necrosis factor alpha levels in patients with gastric cancer. Tumour Biol 37, 405-412
  24. Chang WJ, Du Y, Zhao X, Ma LY and Cao GW (2014) Inflammation-related factors predicting prognosis of gastric cancer. World J Gastroenterol 20, 4586-4596
  25. Nishida A, Andoh A, Inatomi O and Fujiyama Y (2009) Interleukin-32 expression in the pancreas. J Biol Chem 284, 17868-17876
  26. van Hogezand RA, Eichhorn RF, Choudry A, Veenendaal RA and Lamers CB (2002) Malignancies in inflammatory bowel disease: fact or fiction? Scand J Gastroenterol Suppl, 48-53
  27. Yun HM, Park KR, Kim EC, Han SB, Yoon DY and Hong JT (2015) IL-32alpha suppresses colorectal cancer development via TNFR1-mediated death signaling. Oncotarget 6, 9061-9072
  28. Tanaka T, Kohno H, Suzuki R, Yamada Y, Sugie S and Mori H (2003) A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci 94, 965-973
  29. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y and Nakaya R (1990) A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98, 694-702
  30. Yang Y, Wang Z, Zhou Y, Wang X, Xiang J and Chen Z (2015) Dysregulation of over-expressed IL-32 in colorectal cancer induces metastasis. World J Surg Oncol 13, 146
  31. Khawar MB, Mukhtar M, Abbasi MH, Sheikh N (2017) IL-$32{\theta}$: a recently identified anti-inflammatory variant of IL-32 and its preventive role in various disorders and tumor suppressor activity. Am J Transl Res 9, 4726-4737
  32. Catalan V, Gomez-Ambrosi J, Rodriguez A et al (2017) IL-$32{\alpha}$-induced inflammation constitutes a link between obesity and colon cancer. Oncoimmunology 6, e1328338
  33. Sherman M and Klein A (2004) AASLD single-topic research conference on hepatocellular carcinoma: Conference proceedings. Hepatology 40, 1465-1473
  34. Xu H, Zhang S, Pan X et al (2016) TIMP-1 expression induced by IL-32 is mediated through activation of AP-1 signal pathway. Int Immunopharmacol 38, 233-237
  35. Kim SH, Han SY, Azam T, Yoon DY and Dinarello CA (2005) Interleukin-32: a cytokine and inducer of TNFalpha. Immunity 22, 131-142
  36. Kudo M, Ogawa E, Kinose D et al (2012) Oxidative stress induced interleukin-32 mRNA expression in human bronchial epithelial cells. Respir Res 13, 19
  37. Dinarello CA and Kim SH (2006) IL-32, a novel cytokine with a possible role in disease. Ann Rheum Dis 65 Suppl 3, iii61-64
  38. Pan X, Cao H, Lu J et al (2011) Interleukin-32 expression induced by hepatitis B virus protein X is mediated through activation of NF-kappaB. Mol Immunol 48, 1573-1577
  39. Moschen AR, Fritz T, Clouston AD et al (2011) Interleukin-32: a new proinflammatory cytokine involved in hepatitis C virus-related liver inflammation and fibrosis. Hepatology 53, 1819-1829
  40. Kang YH, Park MY, Yoon DY et al (2012) Dysregulation of overexpressed IL-32alpha in hepatocellular carcinoma suppresses cell growth and induces apoptosis through inactivation of NF-kappaB and Bcl-2. Cancer Lett 318, 226-233
  41. Zhao WB, Wang QL, Xu YT, Xu SF, Qiu Y, Zhu F (2018) Overexpression of interleukin-$32{\alpha}$ promotes invasion by modulating VEGF in hepatocellular carcinoma. Oncol Rep. 39, 1155-1162
  42. Iliaz R, Akyuz U, Tekin D et al (2016) Role of several cytokines and adhesion molecules in the diagnosis and prediction of survival of hepatocellular carcinoma. Arab J Gastroenterol 17, 164-167
  43. Kim DH, Park ES, Lee AR et al (2018) Intracellular interleukin-32gamma mediates antiviral activity of cytokines against hepatitis B virus. Nat Commun 9, 3284
  44. Sato M, Shames DS, Gazdar AF and Minna JD (2007) A translational view of the molecular pathogenesis of lung cancer. J Thorac Oncol 2, 327-343
  45. Zeng Q, Li S, Zhou Y et al (2013) Interleukin-32 contributes to invasion and metastasis of primary lung adenocarcinoma via NF-kappaB induced matrix metalloproteinases 2 and 9 expression. Cytokine 65, 24-32
  46. Sorrentino C and Di Carlo E (2009) Expression of IL-32 in human lung cancer is related to the histotype and metastatic phenotype. Am J Respir Crit Care Med 180, 769-779
  47. Wang Y, Yang Y, Zhu Y, Li L, Chen F and Zhang L (2017) Polymorphisms and expression of IL-32: impact on genetic susceptibility and clinical outcome of lung cancer. Biomarkers 22, 165-170
  48. Yun J, Park MH, Son DJ et al (2018) IL-32 gamma reduces lung tumor development through upregulation of TIMP-3 overexpression and hypomethylation. Cell Death Dis 9, 306
  49. Park JS, Choi SY, Lee JH et al (2013) Interleukin-32beta stimulates migration of MDA-MB-231 and MCF-7cells via the VEGF-STAT3 signaling pathway. Cell Oncol (Dordr) 36, 493-503
  50. Park JS, Lee S, Jeong AL et al (2014) Hypoxia-induced IL-32beta increases glycolysis in breast cancer cells. Cancer Lett 356, 800-808
  51. Ainscough JS, Frank Gerberick G, Zahedi-Nejad M et al (2014) Dendritic cell IL-1alpha and IL-1beta are polyubiquitinated and degraded by the proteasome. J Biol Chem 289, 35582-35592
  52. Yong HJ, Park JS, Lee Jeong A et al (2017) Von Hippel-Lindau regulates interleukin-32beta stability in ovarian cancer cells. Oncotarget 8, 69833-69846
  53. Ternette N, Olde Nordkamp MJM, Muller J et al (2018) Immunopeptidomic profiling of HLA-A2-positive triple negative breast cancer identifies potential immunotherapy target antigens. Proteomics 18, e1700465
  54. Lee S, Kim JH, Kim H et al (2010) Activation of the interleukin-32 pro-inflammatory pathway in response to human papillomavirus infection and over-expression of interleukin-32 controls the expression of the human papillomavirus oncogene. Immunology 132, 410-420
  55. Lee S, Kim H, Kang JW et al (2011) The biflavonoid amentoflavone induces apoptosis via suppressing E7 expression, cell cycle arrest at sub-G(1) phase, and mitochondria-emanated intrinsic pathways in human cervical cancer cells. J Med Food 14, 808-816
  56. Goda C, Kanaji T, Kanaji S et al (2006) Involvement of IL-32 in activation-induced cell death in T cells. Int Immunol 18, 233-240
  57. Zhang F, Suarez G, Sha J, Sierra JC, Peterson JW and Chopra AK (2009) Phospholipase A2-activating protein (PLAA) enhances cisplatin-induced apoptosis in HeLa cells. Cell Signal 21, 1085-1099
  58. Cui Y, Sun Z, Li X et al (2016) Expression and clinical significance of cyclooxygenase-2 and interleukin-32 in primary gastric B-cell lymphoma. Oncol Lett 11, 693-698
  59. Yamac D, Ayyildiz T, Coskun U et al (2008) Cyclooxygenase-2 expression and its association with angiogenesis, Helicobacter pylori, and clinicopathologic characteristics of gastric carcinoma. Pathol Res Pract 204, 527-536
  60. Konturek PC, Hartwich A, Zuchowicz M et al (2000) Helicobacter pylori, gastrin and cyclooxygenases in gastric cancer. J Physiol Pharmacol 51, 737-749
  61. Lee S, Kim JH, Kim H et al (2011) Activation of the interleukin-32 pro-inflammatory pathway in response to human papillomavirus infection and over-expression of interleukin-32 controls the expression of the human papillomavirus oncogene. Immunology 132, 410-420
  62. van Kester MS, Borg MK, Zoutman WH et al (2012) A meta-analysis of gene expression data identifies a molecular signature characteristic for tumor-stage mycosis fungoides. J Invest Dermatol 132, 2050-2059
  63. Suga H, Sugaya M, Miyagaki T et al (2013) The role of IL-32 in cutaneous T-cell lymphoma. J Invest Dermatol 134, 1428-1435
  64. Cheon S, Lee JH, Park S et al (2011) Overexpression of IL-32alpha increases natural killer cell-mediated killing through up-regulation of Fas and UL16-binding protein 2 (ULBP2) expression in human chronic myeloid leukemia cells. J Biol Chem 286, 12049-12055
  65. Raulet DH (2003) Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 3, 781-790
  66. Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR and Raulet DH (2002) The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity 17, 19-29
  67. Park MH, Song MJ, Cho MC et al (2011) Interleukin-32 enhances cytotoxic effect of natural killer cells to cancer cells via activation of death receptor 3. Immunology 135, 63-72
  68. Smyth MJ, Cretney E, Takeda K et al (2001) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J Exp Med 193, 661-670
  69. Screpanti V, Wallin RP, Grandien A and Ljunggren HG (2005) Impact of FASL-induced apoptosis in the elimination of tumor cells by NK cells. Mol Immunol 42, 495-499
  70. Yun HM, Oh JH, Shim JH et al (2013) Antitumor activity of IL-32beta through the activation of lymphocytes, and the inactivation of NF-kappaB and STAT3 signals. Cell Death Dis 4, e640
  71. Oh JH, Cho MC, Kim JH et al (2011) IL-32gamma inhibits cancer cell growth through inactivation of NF-kappaB and STAT3 signals. Oncogene 30, 3345-3359
  72. Qu Y, Taylor JL, Bose A and Storkus WJ (2011) Therapeutic effectiveness of intratumorally delivered dendritic cells engineered to express the pro-inflammatory cytokine, interleukin (IL)-32. Cancer Gene Ther 18, 663-673
  73. Ohmatsu H, Humme D, Gonzalez J et al (2017) IL-32 induces indoleamine 2,3-dioxygenase+CD1c+ dendritic cells and indoleamine 2,3-dioxygenase+CD163+ macrophages: Relevance to mycosis fungoides progression. Oncoimmunology 6, e1181237
  74. Chang CJ, Chien Y, Lu KH et al (2011) Oct4-related cytokine effects regulate tumorigenic properties of colorectal cancer cells. Biochem Biophys Res Commun 415, 245-251
  75. Moldenhauer A, Futschik M, Lu H et al (2011) Interleukin 32 promotes hematopoietic progenitor expansion and attenuates bone marrow cytotoxicity. Eur J Immunol 41, 1774-1786


Supported by : National Research Foundation of Korea