Effect of nutrient starvation on proliferation and cytokine secretion of peripheral blood lymphocytes

Ota,Yoshiko; Ishihara,Soichiro; Otani,Kensuke; Yasuda,Koji; Nishikawa,Takeshi; Tanaka,Toshiaki; Tanaka,Junichiro; Kiyomatsu,Tomomichi; Kawai,Kazushige; Hata,Keisuke; Nozawa,Hiroaki; Kazama,Shinsuke; Yamaguchi,Hironori; Sunami,Eiji; Kitayama,Joji; Watanabe,Toshiaki

doi:10.3892/mco.2016.763

Effect of nutrient starvation on proliferation and cytokine secretion of peripheral blood lymphocytes

Authors:
- Yoshiko Ota
- Soichiro Ishihara
- Kensuke Otani
- Koji Yasuda
- Takeshi Nishikawa
- Toshiaki Tanaka
- Junichiro Tanaka
- Tomomichi Kiyomatsu
- Kazushige Kawai
- Keisuke Hata
- Hiroaki Nozawa
- Shinsuke Kazama
- Hironori Yamaguchi
- Eiji Sunami
- Joji Kitayama
- Toshiaki Watanabe
View Affiliations

Affiliations: Department of Surgical Oncology, The University of Tokyo Hospital, Tokyo 113‑8655, Japan
Published online on: February 3, 2016 https://doi.org/10.3892/mco.2016.763
Pages: 607-610

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Proliferating cancer cells are exposed to nutrient deprivation. Numerous previous studies have demonstrated how nutrient deprivation affects cancer cells; however, immune cells exposed to the identical conditions have not been completely examined. Furthermore, T‑helper 2 lymphocyte predominance in certain neoplastic diseases has been reported; however, the mechanism remains unclear. The present study aimed to confirm whether nutrient deprivation affected proliferation and cytokine secretion of peripheral blood lymphocytes (PBLs). The proliferation of PBLs from healthy donors, cultured in a medium containing various glucose levels, was assessed by 3‑(4,5‑dimethylthiazol-2‑yl)-5-(3‑carboxymethoxyphenyl)-2‑(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. The expression levels of interleukin (IL)‑4 and interferon (IFN)‑γ among CD4(+) T cells, cultured with or without glucose and activated with phorbol 12‑myristate 13‑acetate and ionomycin, were examined using an intracellular cytokine staining method. The proliferation of PBLs cultured in a medium containing <100 mg/dl glucose of the standard blood sugar (BS) level was significantly reduced compared with the proliferation observed in a medium containing a standard BS level or higher. PBLs cultured in a glucose‑free medium contained a significantly higher percentage of IL‑4‑positive and a lower percentage of IFN‑γ‑positive CD4(+) T cells compared with those cultured in a high‑glucose medium. Nutrient deprivation suppressed the proliferation of PBLs, fostered the secretion of IL‑4 and reduced secretion of IFN‑γ. It is therefore possible that glucose‑deficient microenvironments in local cancer tissues cause a partial immunodeficiency, which is advantageous to cancer growth.

View Figures

View References

1	Jain RK: Molecular regulation of vessel maturation. Nat Med. 9:685–693. 2003. View Article : Google Scholar : PubMed/NCBI
2	Vaupel P, Thews O and Hoeckel M: Treatment resistance of solid tumors: Role of hypoxia and anemia. Med Oncol. 18:243–259. 2001. View Article : Google Scholar : PubMed/NCBI
3	Park HR, Tomida A, Sato S, Tsukumo Y, Yun J, Yamori T, Hayakawa Y, Tsuruo T and Shin-ya K: Effect on tumor cells of blocking survival response to glucose deprivation. J Natl Cancer Inst. 96:1300–1310. 2004. View Article : Google Scholar : PubMed/NCBI
4	He L, Li X, Luo HS, Rong H and Cai J: Possible mechanism for the regulation of glucose on proliferation, inhibition and apoptosis of colon cancer cells induced by sodium butyrate. World J Gastroenterol. 13:4015–4018. 2007. View Article : Google Scholar : PubMed/NCBI
5	Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y, Ueno T, Ochiai A and Esumi H: Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancr Res. 67:9677–9684. 2007. View Article : Google Scholar
6	Ferraro E and Cecconi F: Autophagic and apoptotic response to stress signals in mammalian cells. Arch Biochem Biophys. 462:210–219. 2007. View Article : Google Scholar : PubMed/NCBI
7	Naor D: Suppressor cells: Permitters and promoters of malignancy? Adv Cancer Res. 29:45–125. 1979. View Article : Google Scholar : PubMed/NCBI
8	Fearon ER, Pardoll DM, Itaya D, Golumbek P, Levitsky HI, Simons JW, Karasuyama H, Vogelstein B and Frost P: Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell. 60:397–403. 1990. View Article : Google Scholar : PubMed/NCBI
9	Tada T, Ohzeki S, Utsumi K, Takiuchi H, Muramatsu M, Li XF, Shimizu J, Fujiwara H and Hamaoka T: Transforming growth factor-beta-induced inhibition of T cell function. Susceptibility difference in T cells of various phenotypes and functions and its relevance to immunosuppression in the tumor-bearing state. J Immunol. 146:1077–1082. 1991.PubMed/NCBI
10	Gallimore A and Sakaguchi S: Regelation of tumour immunity by CD25+T cells. Immunology. 107:5–9. 2002. View Article : Google Scholar : PubMed/NCBI
11	Mosmann TR, Cherwinski H, Bond MW, Giedlin MA and Coffman RL: Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 136:2348–2357. 1986.PubMed/NCBI
12	Bottomly K: A functional dichotomy in CD4+ T lymphocytes. Immunol Today. 9:268–273. 1988. View Article : Google Scholar : PubMed/NCBI
13	Mossman TR and Coffman RL: TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 7:145–173. 1989. View Article : Google Scholar : PubMed/NCBI
14	Kupfer A and Singer SJ: Cell biology of cytotoxic and helper T cell functions. Annu Rev Immunol. 7:309–337. 1989. View Article : Google Scholar : PubMed/NCBI
15	Romagnani S: Lymphokine production by human T cells in dease state. Annu Rev Immunol. 12:227–257. 1994. View Article : Google Scholar : PubMed/NCBI
16	Berner B, Akça D, Jung T, Muller GA and Reuss-Borst MA: Analysis of Th1 and Th2 cytokines expressing CD4+ and CD8+ T cells in rheumatoid arthritis by flow cytometry. J Rheumatol. 27:1128–1135. 2000.PubMed/NCBI
17	Kim J, Modlin RL, Moy RL, Dubinett SM, McHugh T, Nickoloff BJ and Uyemura K: IL-10 production in cutaneous basal and squamous cell carcinoma. A mechanism for evading the local T cell immune response. J Immunol. 155:2240–2247. 1995.PubMed/NCBI
18	Elsässer-Beile U, von Kleist S, Stähle W, et al: Cytikine levels in whole blood cell cultures as parameters of the cellular immunologic activity in patients with malignant melanoma and basal cell carcinoma. Cancer. 71:231–236. 1993. View Article : Google Scholar : PubMed/NCBI
19	Hata H, Xiao H, Petrucci MT, Woodliff J, Chang R and Epstein J: Interleukin-6 gene expression in multiple myeloma: A characteristic of immature tumor cells. Blood. 81:3357–3364. 1993.PubMed/NCBI
20	Pellegrini P, Berghella AM, Del Beato T, Cicia S, Adorno D and Casciani CU: Disregulation in TH1 and TH2 subsets of CD4+ T cells in peripheral blood of colorectal cancer patients and involvement in cancer establishment and progression. Cancer Immunol Immunother. 42:1–8. 1996. View Article : Google Scholar : PubMed/NCBI
21	Berghella AM, Pellegrini P, Del Beato T, Marini M, Tomei E, Adorno D and Casciani CU: The significance of an increase in soluble interleukin-2 receptor level in colorectal cancer and its biological regulating role in the physiological switching of the immune response cytokine network from TH1 to TH2 and back. Cancer Immunol Immunother. 45:241–249. 1998. View Article : Google Scholar : PubMed/NCBI
22	Nakayama H, Kitayama J, Muto T and Nagawa H: Characterization of intracellular cytokine profile of CD4(+) T cells in peripheral blood and tumor-draining lymph nodes of patients with gastrointestinal cancer. Jpn J Clin Oncol. 30:301–305. 2000. View Article : Google Scholar : PubMed/NCBI
23	Sato M, Goto S, Kaneko R, Ito M, Sato S and Takeuchi S: Impaired production of Th1 cytokines and increased frequency of Th2 subsets in PBMC from advanced cancer patients. Anticancer Res. 18:3951–3955. 1998.PubMed/NCBI