NK cell-produced IFN-γ regulates cell growth and apoptosis of colorectal cancer by regulating IL-15

Feng Cui; Di Qu; Ruya Sun; Mingming Zhang; Kejun Nan

doi:10.3892/etm.2019.8343

NK cell-produced IFN-γ regulates cell growth and apoptosis of colorectal cancer by regulating IL-15

Exp Ther Med. 2020 Feb;19(2):1400-1406. doi: 10.3892/etm.2019.8343. Epub 2019 Dec 18.

Authors

Feng Cui^{1

2}, Di Qu¹, Ruya Sun¹, Mingming Zhang¹, Kejun Nan²

Affiliations

¹ Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
² Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shannxi 710061, P.R. China.

Abstract

Globally, colorectal cancer (CC) is the third leading cause of mortality associated with cancer. Natural killer (NK) cells are a major class of cells that are responsible for eliminating tumor cells and cytokine production. NK cell-mediated production of interferon gamma (IFN-γ) has antiviral, immunoregulatory and anti-tumor properties. IL-15 is important in linking inflammation with cancer. For instance, IL-15 promotes humoral and cell-mediated immune responses to inhibit tumor growth. IL-15 inhibits colitis-associated colon carcinogenesis by inducing antitumor immunity. However, the effect of NK cell-mediated IFN-γ on IL-15 expression in CC progression remains unknown. mRNA and protein level were detected using reverse transcription-quantitative PCR and western blotting, respectively. IFN-γ concentrations were detected using ELISAs. The cytotoxicity of NK-92 cells on SW480 cells was detected using cytoTox 96^® non-radioactive cytotoxicity assays. Cell apoptosis and cell proliferation was detected using flow cytometry and CCK-8 assays, respectively. IL-2 was used for NK-92 stimulation, IL-15 antibodies were used to neutralize IL-15 bioactivity. For the present study, 21 patients with CC and 21 healthy volunteers were enrolled at the First Affiliated Hospital of Xi'an Jiaotong University. IL-15 mRNA and protein expression were significantly lower in NK cells isolated from the CC group compared with healthy volunteer group. IL-2 enhanced the production/secretion of IFN-γ in addition to enhancing NK-92 cell-mediated killing of SW480 cells. Compared with the control group, NK-92 cells treated with IL-2 alone significantly increased cell apoptosis, BAX expression levels as well as phosphorylated (p)-Janus kinase 2 and p-STAT1 protein levels, whilst reducing cell viability and Bcl-2 protein levels in SW480 cells. These observations were not made when treated with IL-2 and polyclonal antibody (pAb) targeting IL-15. Taken together, NK cell-mediated IFN-γ served a pivotal role in CC by regulating IL-15. The effects of IL-2 induced IFN-γ were abolished by pAb IL-15 treatment. The mechanisms of action behind how IFN-γ regulates IL-2 is unclear, and is a promising area for future research.

Keywords: cell apoptosis; cell growth; colorectal cancer; interferon-γ.