Yinsheng Wan

Activation of IKK by thymosin α1 requires the TRAF6 signalling pathway

Thymosin α1 (Tα1) is noted for its immunomodulatory activities and therapeutic potential in treatment of infectious diseases and cancer. However, the molecular mechanism of its effectiveness is not completely understood. Here, we report that Tα1 induces interleukin (IL)‐6 expression through the IκB kinase (IKK) and nuclear factor‐κB (NF‐κB) pathway. Using IKKβ‐deficient bone‐marrow‐derived macrophages and mouse embryo fibroblasts (MEFs), we show that IKKβ is essential for IKK and NF‐κB activation as well as efficient IL‐6 induction. Further analysis using tumour necrosis factor receptor‐associated factor 6 (TRAF6)‐deficient MEFs shows that TRAF6 is crucial for activation of IKK and induction of IL‐6 by Tα1. Intriguingly, Tα1 triggers protein kinase C (PKC)ι/ζ activation, which is TRAF6 dependent and involves IKK. In addition, Tα1 induces the formation of a signalsome composed of TRAF6, p62 and PKCι/ζ as well as IKK. Thus, our study identifies Tα1 as a unique activator of the TRAF6 signal pathway and provides a cohesive interpretation of the molecular basis of the therapeutic utility of Tα1.

Signaling Pathways Leading to the Activation of IKK and MAPK by Thymosin α1

Abstract:u2002 Thymosin alpha 1 (Tα1) has therapeutic potential in the treatment of infectious diseases and cancer. However, the exact molecular pathways for Tα1 action are not fully understood. We found that Tα1 induces the production of interleukin‐6 (IL‐6), IL‐10, and IL‐12 in murine bone marrow‐derived macrophages (BMDMs) through IKK and MAPK pathways. Tα1 triggers the activation of AP‐1 and the phosphorylation of JNK and p38. Inhibition of p38 impairs IL‐6 production in response to Tα1. Further, TRAF6 is involved in the activation of JNK and IRAK4 is involved for the activation of IKK and PKCζ in a Tα1‐induced system. Loss of IRAK4 largely blocked induction of IL‐6. Thus, our studies define early signal events that are critical for the Tα1‐induced immune responses.

Correction: EGFR-mediated expression of aquaporin-3 is involved in human skin fibroblast migration

Volume 400(2), pages 225–234nnIn Figure 5 of the original paper, the authors mistakenly duplicated some panels. The authors have repeated the experiment and a new Figure 5 is shown here. nnnnFigurexa05. AQP3 knockdown reduces EGF-induced AQP3 expression and cell migration in human skin fibroblasts.nCells were treated with EGF (100u2005ng/ml) …