title: Effect of exposure to interleukin-21 at various time points on human natural killer cell culture.
abstract: OBJECTIVE
  Interleukin-21 (IL-21) can enhance the effector function of natural killer (NK) cells but also limits their proliferation when continuously combined with IL-2/IL-15. Paradoxically, membrane-bound (mb)-IL-21 has been shown to improve human NK cell proliferation when cultured with IL-2/mb-IL-15. To clarify the role of IL-21, we investigated the effect of the timing of IL-21 addition to NK cell culture.
  
  
  METHODS
  IL-2/IL-15-activated NK cells were additionally treated with IL-21 according to the following schedules; (i) control (without IL-21); (ii) first week (day 0 to day 7); (iii) intermittent (the first 3 days of each week for 7 weeks); (iv) after 1 week (day 8 to day 14); and (v) continuous (day 0 to day 49). The expression of NK receptors, granzyme B, perforin, CD107a, interferon-γ, telomere length and NK cell death were measured by flow cytometry.
  
  
  RESULTS
  Compared with the control (2004.2-fold; n = 10 healthy donors) and intermittent groups (2063.9-fold), a strong proliferative response of the NK cells on day 42 was identified in the "first week" group (3743.8-fold) (P < 0.05). NK cells treated with IL-21 in the "first week" group showed cytotoxicity similar to that in control cells. On day 28, there was a significant increase in cytotoxicity of "first week" NK cells that received IL-21 treatment for an additional 2 days compared with the "first week" NK cells (P < 0.05).
  
  
  CONCLUSIONS
  These data suggest that controlling temporal exposure of IL-21 during NK cell proliferation can be a critical consideration to improve the yields and cytotoxicity of NK cells.
authors.affiliation: Department of Surgery, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Dong-Pyo
authors.initials: DP
authors.lastname: Lim
authors.affiliation: Research Center for Cancer Immunotherapy, Chonnam National University, Hwasun Hospital, Jeollanam-do, Korea.
authors.forename: Youn-Young
authors.initials: YY
authors.lastname: Jang
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Seokho
authors.initials: S
authors.lastname: Kim
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Sang Seok
authors.initials: SS
authors.lastname: Koh
authors.affiliation: Research Center for Cancer Immunotherapy, Chonnam National University, Hwasun Hospital, Jeollanam-do, Korea.
authors.forename: Je-Jung
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Companion & Laboratory Animal Science, Kongju National University, Yesan, Korea.
authors.forename: Ju-Sun
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Korea; Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, Korea.
authors.forename: Minh-Trang
authors.initials: MT
authors.lastname: Thi Phan
authors.affiliation: Research Center for Cancer Immunotherapy, Chonnam National University, Hwasun Hospital, Jeollanam-do, Korea; Department of Companion & Laboratory Animal Science, Kongju National University, Yesan, Korea.
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Shin
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Myung-Geun
authors.initials: MG
authors.lastname: Shin
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Meesun
authors.initials: M
authors.lastname: Yoon
authors.affiliation: Department of Companion & Laboratory Animal Science, Kongju National University, Yesan, Korea.
authors.forename: Sang-Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Surgery, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Jung-Han
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Surgery, Chonnam National University Medical School, Gwangju, Korea. Electronic address: mhpark@chonnam.ac.kr.
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Park
authors.affiliation: Research Center for Cancer Immunotherapy, Chonnam National University, Hwasun Hospital, Jeollanam-do, Korea; Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Korea; Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, Korea. Electronic address: dcho@chonnam.ac.kr.
authors.forename: Duck
authors.initials: D
authors.lastname: Cho
mesh_terms: D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D054353:Perforin / Q000378:metabolism; D059505:Telomere Homeostasis / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D000098546:Interleukin-21
chemical_list: D019409:Interleukin-15; D007376:Interleukin-2; D007378:Interleukins; D054353:Perforin; D007371:Interferon-gamma; D000098546:Interleukin-21
keywords: IL-15; IL-2; IL-21; natural killer cells