Activation of IKK by thymosin α1 requires the TRAF6 signalling pathway

Thymosin alpha 1 (T alpha 1) 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 T alpha 1 induces interleukin (IL)-6 expression through the I kappa B kinase (IKK) and nuclear factor-kappa B (NF-kappa B) pathway. Using IKK beta-deficient bone-marrow-derived macrophages and mouse embryo fibroblasts (MEFs), we show that IKK beta is essential for IKK and NF-kappa B 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 T alpha 1. Intriguingly, Ta1 triggers protein kinase C (PKC)iota/zeta activation, which is TRAF6 dependent and involves IKK. In addition, T alpha 1 induces the formation of a signalsome composed of TRAF6, p62 and PKC iota/zeta as well as IKK. Thus, our study identifies T alpha 1 as a unique activator of the TRAF6 signal pathway and provides a cohesive interpretation of the molecular basis of the therapeutic utility of T alpha 1.