Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지
DOI QR코드

DOI QR Code

Role of Interleukin(IL)-6 in NK Activity to Hypoxic-Induced Highly Invasive Hepatocellular Carcinoma(HCC) Cells

  • Hwan Hee Lee (Department of Pharmacy, Duksung Women's University) ;
  • Hyojung Kang (Vessel-Organ Interaction Research Center, VOICE (MRC), Cancer Research Institute, College of Pharmacy, Kyungpook National University) ;
  • Hyosun Cho (Department of Pharmacy, Duksung Women's University)
  • Received : 2023.04.14
  • Accepted : 2023.06.01
  • Published : 2023.07.28
Download PDF
⟨ Previous Next ⟩

Abstract

Natural killer (NK) cell dysfunctions against hepatocellular carcinoma (HCC) in a hypoxic environment. Many solid tumors are present in a hypoxic condition, which changes the effector function of various immune cells. The transcription of hypoxic-inducible factors (HIFs) in cancer cells make it possible to adapt to their hypoxic environment and to escape the immune surveillance of NK cells. Recently, the correlation between the transcription of HIF-1α and pro-inflammatory cytokines has been reported. Interleukin (IL)-6 is higher in cancers with a highly invasive ability, and is closely related to the metastasis of cancers. This study showed that the expression of HIF-1α in HCC cells was associated with the presence of IL-6 in the environment of HCC-NK cells. Blocking of IL-6 by antibody in the HCC-NK interaction changed the production of several cytokines including TGF-β, IL-1, IL-18 and IL-21. Interestingly, in a co-culture of HIF-1α-expressed HCC cells and NK cells, blocking of IL-6 increased the production of IL-21 in their supernatants. In addition, the absence of IL-6 significantly enhanced the cytotoxic ability and the expression of the activating receptors (NKG2D, NKp44, and NKG2C) in NK cells to HIF-1α-expressed HCC cells. These effects might be made by the decreased expression of HIF-1α in HCC cells through the inhibited phosphorylation of STAT3. In conclusion, the absence of IL-6 in the interaction of HIF-1α-expressed HCC cells and NK cells could enhance the antitumor activity of NK cells to HCC cells.

Keywords

Acknowledgement

This study was supported by the Priority Research Center Program through the NRF funded by the Korean Ministry of Education, Science, and Technology (2016R1A6A1A03007648), the Basic Science Research Program of the National Research Foundation of Korea (NRF) (NRF-2020R1I1A1A01074412). This research was also funded by the 4th BK21 project (Educational Research Group for Platform development of management of emerging infectious diseases) funded the Korean ministry of education (5199990614732).

References

  1. Yuan Y, Jiang YC, Sun CK, Chen QM. 2016. Role of the tumor microenvironment in tumor progression and the clinical applications (Review). Oncol. Rep. 35: 2499-2515. https://doi.org/10.3892/or.2016.4660
  2. Zhang W, Borcherding N, Kolb R. 2020. IL-1 Signaling in tumor microenvironment. Adv. Exp. Med. Biol. 1240: 1-23. https://doi.org/10.1007/978-3-030-38315-2_1
  3. Balkwill FR, Lee A, Aldam G, Moodie E, Thomas JA, Tavernier J, et al. 1986. Human tumor xenografts treated with recombinant human tumor necrosis factor alone or in combination with interferons. Cancer Res. 46: 3990-3993.
  4. Magidey-Klein K, Cooper TJ, Kveler K, Normand R, Zhang T, Timaner M, et al. 2021. IL-6 contributes to metastatic switch via the differentiation of monocytic-dendritic progenitors into prometastatic immune cells. J. ImmunoTher. Cancer 9: e002856.
  5. Shacter E, Arzadon GK, Williams J. 1992. Elevation of interleukin-6 in response to a chronic inflammatory stimulus in mice: inhibition by indomethacin. Blood 80: 194-202. https://doi.org/10.1182/blood.V80.1.194.194
  6. Lee HH, Jung J, Moon A, Kang H, Cho H. 2019. Antitumor and anti-invasive effect of apigenin on human breast carcinoma through suppression of IL-6 expression. Int. J. Mol. Sci. 20: 3143.
  7. Shakiba E, Ramezani M, Sadeghi M. 2018. Evaluation of serum interleukin-6 levels in hepatocellular carcinoma patients: a systematic review and meta-analysis. Clin. Exp. Hepatol. 4: 182-190. https://doi.org/10.5114/ceh.2018.78122
  8. Soresi M, Giannitrapani L, D'Antona F, Florena AM, La Spada E, Terranova A, et al. 2006. Interleukin-6 and its soluble receptor in patients with liver cirrhosis and hepatocellular carcinoma. World J. Gastroenterol. 12: 2563-2568. https://doi.org/10.3748/wjg.v12.i16.2563
  9. Doherty DG, O'Farrelly C. 2000. Innate and adaptive lymphoid cells in the human liver. Immunol. Rev. 174: 5-20. https://doi.org/10.1034/j.1600-0528.2002.017416.x
  10. Malmberg KJ, Carlsten M, Bjorklund A, Sohlberg E, Bryceson YT, Ljunggren HG. 2017. Natural killer cell-mediated immunosurveillance of human cancer. Semin. Immunol. 31: 20-29. https://doi.org/10.1016/j.smim.2017.08.002
  11. Mikulak J, Bruni E, Oriolo F, Di Vito C, Mavilio D. 2019. Hepatic natural killer cells: organ-specific sentinels of liver immune homeostasis and physiopathology. Front. Immunol. 10: 946.
  12. Lee HH, Kang H, Cho H. 2017. Natural killer cells and tumor metastasis. Arch. Pharm. Res. 40: 1037-1049. https://doi.org/10.1007/s12272-017-0951-9
  13. Crane CA, Han SJ, Barry JJ, Ahn BJ, Lanier LL, Parsa AT. 2010. TGF-beta downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients. Neuro. Oncol. 12: 7-13. https://doi.org/10.1093/neuonc/nop009
  14. Wong JL, Berk E, Edwards RP, Kalinski P. 2013. IL-18-primed helper NK cells collaborate with dendritic cells to promote recruitment of effector CD8+ T cells to the tumor microenvironment. Cancer Res. 73: 4653-4662. https://doi.org/10.1158/0008-5472.CAN-12-4366
  15. Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C, et al. 2004. Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Mol. Cell. Biol. 24: 2875-2889. https://doi.org/10.1128/MCB.24.7.2875-2889.2004
  16. Peng XH, Karna P, Cao Z, Jiang BH, Zhou M, Yang L. 2006. Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J. Biol. Chem. 281: 25903-25914. https://doi.org/10.1074/jbc.M603414200
  17. Van Meir E. 1996. Hypoxia-mediated selection of cells with diminished apoptotic potential to solid tumours. Neurosurgery 39: 878-879. https://doi.org/10.1097/00006123-199610000-00057
  18. Kondo A, Safaei R, Mishima M, Niedner H, Lin X, Howell SB. 2001. Hypoxia-induced enrichment and mutagenesis of cells that have lost DNA mismatch repair. Cancer Res. 61: 7603-7607.
  19. Dai X, Pi G, Yang SL, Chen GG, Liu LP, Dong HH. 2018. Association of PD-L1 and HIF-1α coexpression with poor prognosis in Hepatocellular Carcinoma. Transl. Oncol. 11: 559-566. https://doi.org/10.1016/j.tranon.2018.02.014
  20. Lu Y, Hu J, Sun W, Duan X, Chen X. 2015. Hypoxia-mediated immune evasion of pancreatic carcinoma cells. Mol. Med. Rep. 11: 3666-3672. https://doi.org/10.3892/mmr.2015.3144
  21. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441: 235-238. https://doi.org/10.1038/nature04753
  22. Dang Eric V, Barbi J, Yang H-Y, Jinasena D, Yu H, Zheng Y, et al. 2011. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146: 772-784. https://doi.org/10.1016/j.cell.2011.07.033
  23. Wang L, Yi T, Zhang W, Pardoll DM, Yu H. 2010. IL-17 enhances tumor development in carcinogen-induced skin cancer. Cancer Res. 70: 10112-10120. https://doi.org/10.1158/0008-5472.CAN-10-0775
  24. Chang SH, Mirabolfathinejad SG, Katta H, Cumpian AM, Gong L, Caetano MS, et al. 2014. T helper 17 cells play a critical pathogenic role in lung cancer. Proc. Natl. Acad. Sci. USA 111: 5664-5669. https://doi.org/10.1073/pnas.1319051111
  25. Tobin AJ, Noel NP, Christian SL, Brown RJ. 2021. Lipoprotein lipase hydrolysis products induce pro-inflammatory cytokine expression in triple-negative breast cancer cells. BMC Res. Notes 14: 315.
  26. Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH. 2011. Activating and inhibitory receptors of natural killer cells. Immunol. Cell Biol. 89: 216-224. https://doi.org/10.1038/icb.2010.78
  27. Singh V, Khurana A, Navik U, Allawadhi P, Bharani KK, Weiskirchen R. 2022. Apoptosis and pharmacological therapies for targeting thereof for cancer therapeutics. Sci 4: 15.
  28. Xu S, Yu C, Ma X, Li Y, Shen Y, Chen Y, et al. 2021. IL-6 promotes nuclear translocation of HIF-1α to aggravate chemoresistance of ovarian cancer cells. Eur. J. Pharmacol. 894: 173817.
  29. Croce M, Rigo V, Ferrini S. 2015. IL-21: a pleiotropic cytokine with potential applications in oncology. J. Immunol. Res. 2015: 696578.
  30. Skak K, Frederiksen KS, Lundsgaard D. 2008. Interleukin-21 activates human natural killer cells and modulates their surface receptor expression. Immunology 123: 575-583. https://doi.org/10.1111/j.1365-2567.2007.02730.x
  31. Gotthardt D, Sexl V. 2016. STATs in NK-cells: the good, the bad, and the ugly. Front. Immunol. 7: 694.
  32. Lee HH, Cho H. 2020. Attenuated anti-tumor activity of NK-92 cells by invasive human breast carcinoma MDA-MB-231 cells. Mol. Cell. Toxicol. 16: 139-147. https://doi.org/10.1007/s13273-019-00059-4
  33. Li R, Wen A, Lin J. 2020. Pro-inflammatory cytokines in the formation of the pre-metastatic niche. Cancers 12: 3752.
  34. Heichler C, Scheibe K, Schmied A, Geppert CI, Schmid B, Wirtz S, et al. 2020. STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis. Gut 69: 1269-1282. https://doi.org/10.1136/gutjnl-2019-319200
  35. Silva EM, Mariano VS, Pastrez PRA, Pinto MC, Castro AG, Syrjanen KJ, et al. 2017. High systemic IL-6 is associated with worse prognosis in patients with non-small cell lung cancer. PLoS One 12: e0181125.
  36. Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, et al. 2021. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct. Target. Ther. 6: 263.
  37. Xu J LH, Wu G, Zhu M and Li M. 2021. IL-6/STAT3 Is a promising therapeutic target for hepatocellular carcinoma. Front. Oncol. 11: 760971.
  38. Cifaldi L, Prencipe G, Caiello I, Bracaglia C, Locatelli F, De Benedetti F, et al. 2015. Inhibition of natural killer cell cytotoxicity by interleukin-6: Implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol. 67: 3037-3046. https://doi.org/10.1002/art.39295
  39. Gao Y, Souza-Fonseca-Guimaraes F, Bald T, Ng SS, Young A, Ngiow SF, et al. 2017. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat. Immunol. 18: 1004-1015. https://doi.org/10.1038/ni.3800
  40. Palomares O, Martin-Fontecha M, Lauener R, Traidl-Hoffmann C, Cavkaytar O, Akdis M, et al. 2014. Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-β. Genes Immun. 15: 511-520. https://doi.org/10.1038/gene.2014.45
  41. Jelicic K, Cimbro R, Nawaz F, Huang da W, Zheng X, Yang J, et al. 2013. The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-β1 production and FcRL4 expression. Nat. Immunol. 14: 1256-1265. https://doi.org/10.1038/ni.2746
  42. Terme M, Ullrich E, Aymeric L, Meinhardt K, Desbois M, Delahaye N, et al. 2011. IL-18 induces PD-1-dependent immunosuppression in cancer. Cancer Res. 71: 5393-5399. https://doi.org/10.1158/0008-5472.CAN-11-0993
  43. Li Y, Bleakley M, Yee C. 2005. IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response. J. Immunol. 175: 2261-2269. https://doi.org/10.4049/jimmunol.175.4.2261
  44. Wu J, Gao F-x, Wang C, Qin M, Han F, Xu T, et al. 2019. IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma. J. Exper. Clin. Cancer Res. 38: 321.
  45. Qiu JG, Wang L, Liu WJ, Wang JF, Zhao EJ, Zhou FM, et al. 2019. Apigenin inhibits IL-6 transcription and suppresses esophageal carcinogenesis. Front. Pharmacol. 10: 1002.
  46. Lee HH, Cho H. 2022. Apigenin increases natural killer cytotoxicity to human hepatocellular carcinoma expressing HIF-1α through high interaction of CD95/CD95L. J. Microbiol. Biotechnol. 32: 397-404. https://doi.org/10.4014/jmb.2201.01010
  47. Chouaib S, Noman MZ, Kosmatopoulos K, Curran MA. 2017. Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer. Oncogene. 36: 439-445. https://doi.org/10.1038/onc.2016.225
  48. Noman MZ, Hasmim M, Messai Y, Terry S, Kieda C, Janji B, et al. 2015. Hypoxia: a key player in antitumor immune response. A review in the theme: cellular responses to hypoxia. Am. J. Physiol. Cell Physiol. 309: C569-C579. https://doi.org/10.1152/ajpcell.00207.2015
  49. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. 2014. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exper. Med. 211: 781-790. https://doi.org/10.1084/jem.20131916
  50. Mancino A, Schioppa T, Larghi P, Pasqualini F, Nebuloni M, Chen I-H, et al. 2008. Divergent effects of hypoxia on dendritic cell functions. Blood 112: 3723-3734. https://doi.org/10.1182/blood-2008-02-142091
  51. Laderoute KR, Calaoagan JM, Gustafson-Brown C, Knapp AM, Li GC, Mendonca HL, et al. 2002. The response of c-jun/AP-1 to chronic hypoxia is hypoxia-inducible factor 1 alpha dependent. Mol. Cell. Biol. 22: 2515-2523. https://doi.org/10.1128/MCB.22.8.2515-2523.2002
  52. Conway EM, Collen D, Carmeliet P. 2001. Molecular mechanisms of blood vessel growth. Cardiovasc. Res. 49: 507-521. https://doi.org/10.1016/S0008-6363(00)00281-9
  53. Balsamo M, Manzini C, Pietra G, Raggi F, Blengio F, Mingari MC, et al. 2013. Hypoxia downregulates the expression of activating receptors involved in NK-cell-mediated target cell killing without affecting ADCC. Eur. J. Immunol. 43: 2756-2764. https://doi.org/10.1002/eji.201343448
  54. Sarkar S, Germeraad WT, Rouschop KM, Steeghs EM, van Gelder M, Bos GM, et al. 2013. Hypoxia induced impairment of NK cell cytotoxicity against multiple myeloma can be overcome by IL-2 activation of the NK cells. PLoS One 8: e64835.
  55. Brady J, Hayakawa Y, Smyth MJ, Nutt SL. 2004. IL-21 induces the functional maturation of murine NK cells. J. Immunol. 172: 2048-2058. https://doi.org/10.4049/jimmunol.172.4.2048
  56. de Rham C, Ferrari-Lacraz S, Jendly S, Schneiter G, Dayer J-M, Villard J. 2007. The proinflammatory cytokines IL-2, IL-15 and IL-21 modulate the repertoire of mature human natural killer cell receptors. Arthritis Res. Ther. 9: R125.
  57. Wendt K, Wilk E, Buyny S, Schmidt RE, Jacobs R. 2007. Interleukin-21 differentially affects human natural killer cell subsets. Immunology 122: 486-495. https://doi.org/10.1111/j.1365-2567.2007.02675.x
  58. Gotthardt D, Putz EM, Straka E, Kudweis P, Biaggio M, Poli V, et al. 2014. Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance. Blood 124: 2370-2379. https://doi.org/10.1182/blood-2014-03-564450