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J Leukoc Biol 2011 Jul;90(1):87-97

Interleukin-12 treatment down-regulates STAT4 and induces apoptosis with increasing ROS production in human natural killer cells.

Lei Y, Zhang H, Zhang M, Dayton A


NK cells are prominent mediators of the immunomodulating and antiangiogenic activity of IL-12. However, the effect of prolonged IL-12 treatment on NK cells is unclear. In this study, we observed that IL-12 initially activates NK cells, but prolonged IL-12 treatment specifically down-regulates IL-12 signaling and induces NK cell apoptosis associated with a significant reduction in cytolytic activity and IFN-¿ production in response to further IL-12 stimulation. Further results demonstrate that prolonged IL-12 stimulation of NK cells specifically decreases the level of activated STAT4 protein, a critical IL-12 signaling component, through decreasing STAT4 mRNA and protein levels rather than inducing STAT4 protein degradation. IL-12 treatment induces NK cell activation as well as levels of ROS, but prolonged IL-12 treatment causes ROS accumulation, which in turn, results in the loss of ¿¿(m), the release of cytochrome c, and the activation of caspase-3, resulting in NK cell apoptosis. These findings provide new insights into IL-12 regulation in human NK cells, where IL-12 initially promotes NK cell activation but subsequently limits this response through a negative-feedback mechanism.

Category: Journal Article
PubMed ID: #21543583 DOI: 10.1189/jlb.1210674
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-10-03 Entry Last Modified: 2012-08-29