Gamma‐tocotrienol inhibits cytokine‐stimulated NF‐kB activation by inducing A20 and modulating sphingolipids

Abstract

Nuclear factor‐kB (NF‐kB) plays a central role in inflammation‐associated diseases and cancer. Gamma‐tocotrienol (γTE), a natural form of vitamin E, is known to inhibit NF‐kB activation, but the underlying mechanism has not been identified. Here we show that γTE inhibited cytokine‐triggered activation of NF‐kB and its upstream regulator transforming growth factor β‐activated kinase‐1 in macrophages. gTE induced up‐regulation of A20, an inhibitor of NF‐kB. Knockout of A20 slightly diminished gTE's anti‐NF‐kB effect but gTE increased other NF‐kB inhibitors like Cezanne and phosphatse DUSP14 in A20‐/‐ cells. In search of the reason for A20 upregulation, we found that gTE increased phosphorylation of translation initiation factor 2 (eIF2a), IkBa and JNK, indicating induction of ER stress. Meanwhile, gTE led to accumulation of dihydroceramides, sphingoid bases in de novo synthesis of sphingolipid pathway. Chemical inhibition of de novo sphingolipid synthesis reversed gTE's anti‐NF‐kB effect. The importance of sphingolipid modulation is further supported by the observation that C8‐dihydroceramide mimicked gTE in up‐regulating A20, enhancing ER stress and attenuating TNF‐triggered NF‐kB activation. Our study identifies a novel anti‐NF‐kB mechanism via induction of A20 and modulation of sphingolipids, and demonstrates an immune‐modulatory role of dihydrocermide.