Skip to main content

Advertisement

Log in

Functional roles of cytokines in infectious disease associated colorectal carcinogenesis

  • Mini Review Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Infection processes induce various soluble factors that are carcinogens in humans; therefore, research into the soluble factors of chronic disease released from cells that have been infected with parasites is warranted. Parasitic infections in host cells release high levels of IFNγ. Studies have hypothesised that parasitosis-associated carcinogenesis might be analogous to colorectal cancers developed from inflammatory bowel diseases, whereby various cytokines and chemokines are secreted during chronic inflammation. IL-18 and IL-21 are other factors that might be involved in the development of colorectal cancer in schistosomiasis patients and patients with other infections. IL-21 has profound effects on tumour growth and immunosurveillance of colitis-associated tumourigenesis, thereby emphasising its involvement in the pathogenesis of colorectal cancer. The prominent role of IL-21 in antitumour effects greatly depends on the enhanced cytolytic activity of NK cells and the pathogenic role of IL-21, which is often associated with enhanced risks of cancer and chronic inflammatory processes. As IL-15 is also related to chronic disease, it is believed to also play a role in the antitumour effect of colorectal carcinogenesis. IL-15 generates and maintains long-term CD8+ T cell immunity against T. gondii to control the infection of intracellular pathogens. The lack of IL-15 in mice contributes to the downregulation of the IFNγ-producing CD4+ T cell response against acute T. gondii infection. IL-15 induces hyperplasia and supports the progressive growth of colon cancer via multiple functions. The limited role of IL-15 in the development of NK and CD8+ T cells suggests that there may be other cytokines compensating for the loss of the IL-15 gene.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  1. Ge P, Ong CY, Abdalkareem AE, Khoo BY, Yuan B (2021) IFNγ and IL18 in conditioned media of parasite infected host and IL21 silenced colorectal cancer cells. Exp Ther Med 21(2):103

    Article  CAS  Google Scholar 

  2. Huppert A, Katriel G (2013) Mathematical modelling and prediction in infectious disease epidemiology. Clin Microbiol Infect 19(11):999–1005. https://doi.org/10.1111/1469-0691.12308

    Article  CAS  PubMed  Google Scholar 

  3. Qiu D-C, Hubbard AE, Zhong B, Zhang Y, Spear RC (2005) A matched, case-control study of the association between Schistosoma japonicum and liver and colon cancers, in rural China. Ann Trop Med Parasitol 99(1):47–52. https://doi.org/10.1179/136485905X19883

    Article  PubMed  Google Scholar 

  4. IARC (2011) Monograph on the evaluation of carcinogenic risks to humans. Part B: biological agents, vol 100. World Health Organization, International Agency for Research on Cancer, Lyon, pp 1–487

    Google Scholar 

  5. Kaplanski G (2018) Interleukin-18: biological properties and role in disease pathogenesis. Immunol Rev 281(1):138–153

    Article  CAS  Google Scholar 

  6. Ludwiczek O, Kaser A, Novick D, Dinarello CA, Rubinstein M, Vogel W, Tilg H (2002) Plasma levels of interleukin-18 and interleukin-18 binding protein are elevated in patients with chronic liver disease. J Clin Immunol 22(6):331–337. https://doi.org/10.1023/a:1020600230977

    Article  CAS  PubMed  Google Scholar 

  7. Slattery ML, Lundgreen A, Bondurant KL, Wolff RK (2011) Interferon-signaling pathway associations with colon and rectal cancer risk and subsequent survival. Carcinogenesis 32(11):1660–1667. https://doi.org/10.1093/carcin/bgr189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Naglak EK, Morrison SG, Morrison RP (2016) Gamma interferon is required for optimal antibody-mediated immunity against genital chlamydia infection. Infect Immun 84(11):3232–3242. https://doi.org/10.1128/IAI.00749-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen MC, Chuang CY, Wang FP, Chang PY, Chen YJ, Tang YC, Chou SC (1981) Colorectal cancer and schistosomiasis. Lancet 317(8227):971–973. https://doi.org/10.1016/S0140-6736(81)91734-7

    Article  Google Scholar 

  10. Salim OEH, Hamid HK, Mekki SO, Suleiman SH, Ibrahim SZ (2010) Colorectal carcinoma associated with schistosomiasis: a possible causal relationship. World J Surg Oncol 8:68. https://doi.org/10.1186/1477-7819-8-68

    Article  Google Scholar 

  11. Rosin MP, Anwar WA, Ward AJ (1994) Inflammation, chromosomal instability, and cancer: the schistosomiasis model. Cancer Res 54(7 Suppl):1929s–1933s

    CAS  PubMed  Google Scholar 

  12. Madbouly KM, Senagore AJ, Mukerjee A, Hussein AM, Shehata MA, Navine P, Delaney CP, Fazio VW (2007) Colorectal cancer in a population with endemic Schistosoma mansoni: is this an at-risk population? Int J Colorectal Dis 22(2):175–181. https://doi.org/10.1007/s00384-006-0144-3

    Article  PubMed  Google Scholar 

  13. Goldszmid RS, Dzutsev A, Trinchieri G (2014) Host immune response to infection and cancer: unexpected commonalities. Cell Host Microbe 15(3):295–305. https://doi.org/10.1016/j.chom.2014.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. van Tong H, Brindley PJ, Meyer CG, Velavan TP (2017) Parasite infection, carcinogenesis and human malignancy. EBioMedicine 15:12–23. https://doi.org/10.1016/j.ebiom.2016.11.034

    Article  PubMed  Google Scholar 

  15. Wang L-N, Cui Y-X, Ruge F, Jiang WG (2015) Interleukin 21 and its receptor play a role in proliferation, migration and invasion of breast cancer cells. Cancer Genomics Proteomics 12(5):211–221

    CAS  PubMed  Google Scholar 

  16. Santegoets SJ, Turksma AW, Powell DJ Jr, Hooijberg E, de Gruijl TD (2013) IL-21 in cancer immunotherapy: at the right place at the right time. Oncoimmunology 2(6):e24522. https://doi.org/10.4161/onci.24522

    Article  PubMed  PubMed Central  Google Scholar 

  17. Spolski R, Leonard WJ (2014) Interleukin-21: a double-edged sword with therapeutic potential. Nat Rev Drug Discov 13(5):379–395. https://doi.org/10.1038/nrd4296

    Article  CAS  PubMed  Google Scholar 

  18. Chaplin DD (2010) Overview of the immune response. J Allergy Clin Immunol 125(2 Suppl):S3-23. https://doi.org/10.1016/j.jaci.2009.12.980

    Article  PubMed  PubMed Central  Google Scholar 

  19. Abdalkareem EA, Ong CY, Lim BH, Khoo BY (2018) Neutralizing FGF4 protein in conditioned medium of IL-21-silenced HCT116 cells restores the migratory activity of the colorectal cancer cells. Cytotechnology 70(5):1363–1374. https://doi.org/10.1007/s10616-018-0228-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Abdalkareem EA, Tan GC, Abdalla HS, Lim BH, Khoo BY (2014) Identification of specific proteins in colorectal cancer patients with Schistosoma mansoni infection as a possible biomarker for the treatment of this infection. Asian Pac J Trop Dis 4(Suppl):S720–S724

    Article  Google Scholar 

  21. Stolfi C, Rizzo A, Franzè E, Rotondi A, Fantini MC, Sarra M, Caruso R, Monteleone I, Sileri P, Franceschilli L, Caprioli F, Ferrero S, MacDonald TT, Pallone F, Monteleone G (2011) Involvement of interleukin-21 in the regulation of colitis-associated colon cancer. J Exp Med 208(11):2279–2290

    Article  CAS  Google Scholar 

  22. Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JF, Cheever AW, Young DA, Collins M, Grusby MJ, Wynn TA (2006) The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Investig 116(7):2044–2055. https://doi.org/10.1172/JCI27727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kesselring R, Jauch D, Fichtner-Feigl S (2012) Interleukin 21 impairs tumour immunosurveillance of colitis-associated colorectal cancer. Oncoimmunology 1(4):537–538. https://doi.org/10.4161/onci.19407

    Article  PubMed  PubMed Central  Google Scholar 

  24. Fröhlich A, Marsland BJ, Sonderegger I, Kurrer M, Hodge MR, Harris NL, Kopf M (2007) IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo. Blood 109(5):2023–2031. https://doi.org/10.1182/blood-2006-05-021600

    Article  CAS  PubMed  Google Scholar 

  25. Ariyaratne A, Szabo EK, Bowron J, Finney CAM (2018) Increases in helminth-induced IL-21 protein levels disappear upon sample freezing. Cytokine 108:179–181. https://doi.org/10.1016/j.cyto.2018.04.007

    Article  CAS  PubMed  Google Scholar 

  26. Anthony RM, Rutitzky LI, Urban JF Jr, Stadecker MJ, Gause WC (2007) Protective immune mechanisms in helminth infection. Nat Rev Immunol 7(12):975–987. https://doi.org/10.1038/nri2199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ozaki K, Spolski R, Feng CG, Qi C, Cheng J, Sher A, Morse HC III, Liu C, Schwartzberg PL, Leonard WJ (2002) A critical role for IL-21 in regulating immunoglobulin production. Science 298(5598):1630–1634. https://doi.org/10.1126/science.1077002

    Article  CAS  PubMed  Google Scholar 

  28. Kasaian MT, Whitters MJ, Carter LL, Lowe LD, Jussif JM, Deng B, Johnson KA, Witek JS, Senices M, Konz RF, Wurster AL, Donaldson DD, Collins M, Young DA, Grusby MJ (2002) IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity 16(4):559–569. https://doi.org/10.1016/s1074-7613(02)00295-9

    Article  CAS  PubMed  Google Scholar 

  29. Brady J, Hayakawa Y, Smyth MJ, Nutt SL (2004) IL-21 induces the functional maturation of murine NK cells. J Immunol 172(4):2048–2058. https://doi.org/10.4049/jimmunol.172.4.2048

    Article  CAS  PubMed  Google Scholar 

  30. Roda JM, Parihar R, Lehman A, Mani A, Tridandapani S, Carson WE (2006) Interleukin-21 enhances NK cell activation in response to antibody-coated targets. J Immunol 177(1):120–129. https://doi.org/10.4049/jimmunol.177.1.120

    Article  CAS  PubMed  Google Scholar 

  31. Skak K, Frederiksen KS, Lundsgaard D (2008) Interleukin-21 activates human natural killer cells and modulates their surface receptor expression. Immunology 123(4):575–583. https://doi.org/10.1111/j.1365-2567.2007.02730.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Solaymani-Mohammadi S, Berzofsky JA (2019) Interleukin 21 collaborates with interferon-γ for the optimal expression of interferon-stimulated genes and enhances protection against enteric microbial infection. PLoS Pathog 15(2): e1007614. https://doi.org/10.1371/journal.ppat.1007614

    Article  CAS  Google Scholar 

  33. Fantini MC, Monteleone G, MacDonald TT (2008) IL-21 comes of age as a regulator of effector T cells in the gut. Mucosal Immunol 1(2):110–115. https://doi.org/10.1038/mi.2007.17

    Article  CAS  PubMed  Google Scholar 

  34. Davis MR, Zhu Z, Hansen DM, Bai Q, Fang Y (2015) The role of IL-21 in immunity and cancer. Cancer Lett 358(2):107–114. https://doi.org/10.1016/j.canlet.2014.12.047

    Article  CAS  PubMed  Google Scholar 

  35. Danese S, Malesci A, Vetrano S (2011) Colitis-associated cancer: the dark side of inflammatory bowel disease. Gut 60(12):1609–1610. https://doi.org/10.1136/gutjnl-2011-300953

    Article  CAS  PubMed  Google Scholar 

  36. Nemoto Y, Watanabe M (2012) The Th1, Th2, and Th17 paradigm in inflammatory bowel disease. In: Baumgart D (ed) Crohn’s disease and ulcerative colitis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-0998-4_15

    Chapter  Google Scholar 

  37. Jauch D, Martin M, Schiechl G, Kesselring R, Schlitt HJ, Geissler EK, Fichtner-Feigl S (2011) Interleukin 21 controls tumour growth and tumour immunosurveillance in colitis-associated tumorigenesis in mice. Gut 60(12):1678–1686. https://doi.org/10.1136/gutjnl-2011-300612

    Article  CAS  PubMed  Google Scholar 

  38. Monteleone I, Pallone F, Monteleone G (2009) Interleukin-23 and Th17 cells in the control of gut inflammation. Mediat Inflamm 2009:297645. https://doi.org/10.1155/2009/297645

    Article  Google Scholar 

  39. Saeed S, Revell PA (2001) Production and distribution of Interleukin 15 and its receptors (IL-15Rα and IL-R2β) in the implant interface tissues obtained during revision of failed total joint replacement. Int J Exp Pathol 82(3):201–209. https://doi.org/10.1046/j.1365-2613.2001.iep0082-0201-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dubois S, Mariner J, Waldmann TA, Tagaya Y (2002) IL-15Rα recycles and presents IL-15 in trans to neighbouring cells. Immunity 17(5):537–547. https://doi.org/10.1016/s1074-7613(02)00429-6

    Article  CAS  PubMed  Google Scholar 

  41. Carson WE, Fehniger TA, Haldar S, Eckhert K, Lindemann MJ, Lai CF, Croce CM, Baumann H, Caligiuri MA (1997) A potential role for Interleukin-15 in the regulation of human natural killer cell survival. J Clin Investig 99(5):937–943. https://doi.org/10.1172/JCI119258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Waldmann TA (2015) The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol Res 3(3):219–227. https://doi.org/10.1158/2326-6066.CIR-15-0009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Park JY, Lee SH, Yoon S, Park Y, Jung H, Kim T, Choi I (2011) IL-15-induced IL-10 increases the cytolytic activity of human natural killer cells. Mol Cells 32(3):265–272. https://doi.org/10.1007/s10059-011-1057-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Scala MD, Gil-Fariña I, Olagüe C, Vales A, Sobrevals L, Fortes P, Corbacho D, González-Aseguinolaza G (2016) Identification of IFN-γ-producing T cells as the main mediators of the side effects associated to mouse interleukin-15 sustained exposure. Oncotarget 7(31):49008–49026. https://doi.org/10.18632/oncotarget.10264

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ku CC, Murakami M, Sakamoto A, Kappler J, Marrack P (2000) Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288(5466):675–678. https://doi.org/10.1126/science.288.5466.675

    Article  CAS  PubMed  Google Scholar 

  46. Reinecker HC, MacDermott RP, Mirau S, Dignass A, Podolsky DK (1996) Intestinal epithelial cells both express and respond to interleukin 15. Gastroenterology 111(6):1706–1713. https://doi.org/10.1016/s0016-5085(96)70036-7

    Article  CAS  PubMed  Google Scholar 

  47. Inagaki-Ohara K, Nishimura H, Mitani A, Yoshikai Y (1997) Interleukin-15 preferentially promotes the growth of intestinal intraepithelial lymphocytes bearing gamma delta T cell receptor in mice. Eur J Immunol 27(11):2885–2891. https://doi.org/10.1002/eji.1830271121

    Article  CAS  PubMed  Google Scholar 

  48. Ma LJ, Acero LF, Zal T, Schluns KS (2009) Trans-presentation of IL-15 by intestinal epithelial cells drives development of CD8 alpha alpha IELs. J Immunol 183(2):1044–1054. https://doi.org/10.4049/jimmunol.0900420

    Article  CAS  PubMed  Google Scholar 

  49. Bhadra R, Guan H, Khan IA (2010) Absence of both IL-7 and IL-15 severely impairs the development of CD8+ T cell response against Toxoplasma gondii. PLoS ONE 5(5):e10842. https://doi.org/10.1371/journal.pone.0010842

    Article  Google Scholar 

  50. Hakim FT, Gazzinelli RT, Denkers E, Hieny S, Shearer GM, Sher A (1991) CD8+ T cells from mice vaccinated against Toxoplasma gondii are cytotoxic for parasite-infected or antigen-pulsed host cells. J Immunol 147(7):2310–2316

    CAS  PubMed  Google Scholar 

  51. Gazzinelli R, Xu Y, Hieny S, Cheever A, Sher A (1992) Simultaneous depletiong of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. J Immunol 149(1):175–180

    CAS  PubMed  Google Scholar 

  52. Khan IA, Moretto M, Wei X, Williams M, Schwartzman JD, Liew FY (2002) Treatment with soluble interleukin-15Rα exacerbates intracellular parasitic infection by blocking the development of memory CD8+ T cell response. J Exp Med 195(11):1463–1470. https://doi.org/10.1084/jem.20011915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Combe CL, Moretto MM, Schwartzman JD, Gigley JP, Bzik DJ, Khan IA (2006) Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite. PNAS 103(17):6635–6640

    Article  CAS  Google Scholar 

  54. Lieberman LA, Villegas EN, Hunter CA (2004) Interleukin-15-deficient mice develop protective immunity to Toxoplasma gondii. Infect Immun 72(11):6729–6732. https://doi.org/10.1128/IAI.72.11.6729-6732.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Perera P, Lichy JH, Waldmann TA, Perera LP (2012) The role of interleukin-15 in inflammation and immune responses to infection: implications for its therapeutic use. Microbes Infect 14(3):247–261. https://doi.org/10.1016/j.micinf.2011.10.006

    Article  CAS  PubMed  Google Scholar 

  56. Carrero RM, Beceren-Braun F, Rivas SC, Hegde SM, Gangadharan A, Plote D, Pham G, Anthony SM, Schluns KS (2019) IL-15 is a component of inflammatory milieu in the tumor microenvironment promoting antitumor responses. PNAS 116(2):599–608. https://doi.org/10.1073/pnas.1814642116

    Article  CAS  Google Scholar 

  57. Stevens AC, Matthews J, Andres P, Baffis V, Zheng XX, Chae DW, Smith J, Strom TB, Maslinski W (1997) Interleukin-15 signals T84 colonic epithelial cells in the absence of the interleukin-2 receptor beta-chain. Am J Physiol 272(5Pt1):G1201–G1208. https://doi.org/10.1152/ajpgi.1997.272.5.G1201

    Article  CAS  PubMed  Google Scholar 

  58. Liu Z, Geboes K, Colpaert S, D’Haens GR, Rutgeerts P, Ceuppens JL (2000) IL-15 is highly expressed in inflammatory bowel disease and regulates local T cell-dependent cytokine production. J Immunol 164(7):3608–3615. https://doi.org/10.4049/jimmunol.164.7.3608

    Article  CAS  PubMed  Google Scholar 

  59. Bulfone-Paus S, Ungureanu D, Pohl T, Lindner G, Paus R, Rückert R, Krause H, Kunzendorf U (1997) Interleukin-15 protects from lethal apoptosis in vivo. Nat Med 3(10):1124–1128. https://doi.org/10.1038/nm1097-1124

    Article  CAS  PubMed  Google Scholar 

  60. Angiolillo AL, Kanegane H, Sgadari C, Reaman GH, Tosato G (1997) Interleukin-15 promotes angiogenesis in vivo. Biochem Biophys Res Commun 233(1):231–237. https://doi.org/10.1006/bbrc.1997.6435

    Article  CAS  PubMed  Google Scholar 

  61. Kuniyasu H, Oue N, Nakae D, Tsutsumi M, Denda A, Tsujiuchi T, Yokozaki H, Yasui W (2001) Interleukin-15 expression is associated with malignant potential in colon cancer cells. Pathobiology 69(2):86–95. https://doi.org/10.1159/000048761

    Article  CAS  PubMed  Google Scholar 

  62. Reddy KB, Krueger JS, Kondapaka SB, Diglio CA (1999) Mitogen-activated protein kinase (MAPK) regulates the expression of progelatinase B (MMP-9) in breast epithelial cells. Int J Cancer 82(2):268–273. https://doi.org/10.1002/(SICI)1097-0215(19990719)82:2<268::AID-IJC18>3.0.CO;2-4

    Article  CAS  Google Scholar 

  63. Westermarck J, Kähäri VM (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13(8):781–792

    Article  CAS  Google Scholar 

  64. Finlay D, Healy V, Furlong F, O’Connell FC, Keon NK, Martin F (2000) MAP kinase pathway signalling is essential for extracellular matrix determined mammary epithelial cell survival. Cell Death Differ 7(3):302–313. https://doi.org/10.1038/sj.cdd.4400652

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The first author would like to thank the Graduate Assistant Scheme of Universiti Sains Malaysia.

Funding

The present study was funded by Fundamental Research Grant Scheme Fasa 1/2017 (Grant No. 203/CIPPM/6711599).

Author information

Authors and Affiliations

Authors

Contributions

OCY and EAA made substantial contributions to the design of the present study. KBY revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Boon Yin Khoo.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ong, C.Y., Abdalkareem, E.A. & Khoo, B.Y. Functional roles of cytokines in infectious disease associated colorectal carcinogenesis. Mol Biol Rep 49, 1529–1535 (2022). https://doi.org/10.1007/s11033-021-07006-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-07006-4

Keywords

Navigation