title: Interleukin-12 treatment down-regulates STAT4 and induces apoptosis with increasing ROS production in human natural killer cells.
abstract: 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-γ 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 Δψ(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.
authors.affiliation: Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20892, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: YingFeng
authors.initials: Y
authors.lastname: Lei
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
authors.forename: Andrew
authors.initials: A
authors.lastname: Dayton
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western; D002469:Cell Separation; D015536:Down-Regulation; D025461:Feedback, Physiological / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D017382:Reactive Oxygen Species; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D018664:Interleukin-12