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Downregulation of NF-kB Activity by Tribbles Homolog 3 (TRB3) is Associated with the Suppression of Akt in RAW264.7 Macrophages

Kim, Jaemi; Baik, Eun Joo; Lee, Soo Hwan
Department of Physiology
Tribbles homolog 3 (TRB3), a human homolog of Drosophila tribble, is a pseudokinase whose expression is regulated by stress responses and changes in the nutritional status. It has been reported that TRB3 participates not only in the regulation of normal cellular functions such as energy metabolism but also pathological processes including inflammation and cell death. Previously, we demonstrated that glucose enhancing effect on LPS-induced iNOS expression and NO production could be associated with down-regulation of TRB3. In this study, we explored the crosstalk between signaling pathways responsible for glucose enhancing effect in relation to TRB3. As previously shown, TRB3 expression was significantly reduced under high glucose (25 mM) condition in RAW264.7 cells. High glucose enhanced LPS-induced phosphorylation of Akt and GSK3β. LPS-induced iNOS expression was attenuated by dominant negative Akt (DN-Akt) and an Akt inhibitor (Akti), suggesting the possible role of Akt in glucose enhancing effect. Indeed, overexpression of TRB3, a negative modulator of Akt, resulted in diminution of LPS-induced iNOS expression. Moreover, ectopic expression of TRB3 inhibited LPS-induced IkBa phosphorylation, NF-kB translocation into the nucleus and transcriptional activity of NF-kB, whereas the knock-down of endogenous TRB3 increased these responses. Considering that TLR4 signaling pathway could be modulated by Akt activity, these results suggest that TRB3 downregulates NF-κB activity by blocking Akt and thereby LPS-induced iNOS expression and NO production in RAW264.7 macrophage cells and provide insight into the cellular mechanism of glucose enhancing effect.
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