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Updated: Aug 9, 2026
Expansion, Purification, and Functional Assessment of Human Peripheral Blood NK Cells
Published on: February 3, 2011
Synergistic effects of interleukin 4 and interleukin 12 on NK cell proliferation
B Naume1, M K Gately, B B Desai
1Institute of Cancer Research, University of Trondheim, Norway.
Insights
Interleukin-4 (IL-4) synergizes with Interleukin-12 (IL-12) to significantly boost CD56+ NK cell proliferation and yield. This combination uniquely enhances NK cell expansion without affecting LAK activity, offering new insights into NK cell activation.
Area of Science:
- Immunology
- Cell Biology
- Cytokine Signaling
Background:
- Previous studies show Interleukin-12 (IL-12) and Interleukin-7 (IL-7) induce high LAK activity and low proliferation in CD56+ NK cells.
- The role of Interleukin-4 (IL-4) in modulating IL-12-induced NK cell responses requires further investigation.
Purpose of the Study:
- To investigate the effect of IL-4 on IL-12-induced activation of CD56+ NK cells.
- To determine if IL-4 influences LAK activity, proliferation, and cell yield in response to IL-12.
Main Methods:
- Treatment of CD56+ NK cells with IL-12 alone and in combination with IL-4.
- Assessment of LAK activity, proliferative activity, cell yield, TNF production, and receptor expression (IL-12R, IL-4R).
Main Results:
- IL-4 did not affect IL-12-induced LAK activity but synergistically increased proliferation (8-fold) and cell yield in CD56+ NK cells.
- The synergistic proliferative effect was specific to CD56+ NK cells; CD56- cells were unresponsive.
- Combined IL-4 and IL-12 treatment enhanced IL-12 receptor (IL-12R) and IL-4 receptor (IL-4R) expression on CD56+ NK cells.
Conclusions:
- IL-4 exhibits unique stimulatory properties on resting CD56+ NK cells when used as a costimulus with IL-12.
- The synergistic proliferation is likely mediated by enhanced IL-12R and IL-4R expression induced by the combined cytokines.
- This finding suggests a novel strategy for enhancing NK cell expansion for therapeutic applications.
Abstract:
Our previous studies have demonstrated that interleukin12 (IL-12) (cytotoxic lymphocyte maturation factor/NK cell stimulatory factor) and IL-7 alone have the ability to generate high LAK activity and low proliferative activity in CD56+ NK cells. This study was undertaken to examine the influence of IL-4 on the IL-12-induced activation of CD56+ NK cells. IL-4 did not affect the IL-12-induced generation of LAK activity in CD56+ cells, in contrast to an inhibition of IL-2 and IL-7-induced LAK activity. Most interestingly, the combination of IL-4 and IL-12 resulted in a synergistic proliferative activity (8-fold) in the CD56+ NK cells, and a marked increase in the cell yield at day 5 was detected. Furthermore, the potent effect of IL-4 on IL-12-induced proliferation was restricted to the CD56+ NK cells, as CD56- cell populations were found unresponsive to the combination of IL-4 and IL-12. Furthermore, IL-4 induced a slight increase in the IL-12-stimulated TNF production. IL-12 enhanced the IL-12 receptor (R) expression and IL-4R expression in the CD56+ NK cells. Combined treatment with IL-12 and IL-4 further enhanced the IL-12R expression, most prominently in the CD56+, CD16- NK subpopulation. The increased IL-4R expression induced by IL-12 and the increased IL-12R expression induced by IL-4 may explain the synergistic proliferative activity detected in response to IL-12 and IL-4. IL-4 seems to possess unique stimulatory properties towards resting CD56+ NK cells, when used as a costimulus with IL-12.
