A comparative study of the effects of inhibitory cytokines on human natural killer cells and the mechanistic features of transforming growth factor-beta

• The most suppressive cytokine and its’ mechanisms on NK cells were studied.
• TGF-β potently inhibited the function of NK cells compared to IL-10 and IL-4.
• TGF-β reduced the tyrosine phosphorylation of Syk and the expression of c-myc.
• TGF-β inhibited activated transcription factors and constitutively expressed ones.
• We elucidated the inhibitory mechanisms of NK cells when affected by TGF-β.

The major factors and mechanisms by which natural killer (NK) cells are inhibited in cancer patients have not yet been well defined. In this study, we conducted a comparative analysis of the effects of TGF-β, IL-10, and IL-4 on primary NK cells, and it was demonstrated that (1) TGF-β most potently inhibited the overall function of NK cells. (2) It appears that TGF-β reduced the tyrosine phosphorylation of Syk and the expression of c-myc. (3) It was also found that the IL-2-induced promoter-binding activities of C-myb, AP-1, CREB, and AR were also completely suppressed upon TGF-β treatment. Interestingly, TGF-β also completely suppressed other transcription factors, which are constitutively activated. Among these factors, we further confirmed roles of AP-1 in NK-92 cell activation through c-jun and MEK1 inhibitor assay. Our study provides insight into the effects of TGF-β in modulating NK cell functions.