Activation of IKK by thymosin α1 requires the TRAF6 signalling pathway

Abstract

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.

Protein Kinase C Mediates Enterohemorrhagic Escherichia coli O157:H7-Induced Attaching and Effacing Lesions

“…Cells pretreated with the lower concentration of a concentration-dependent PKC inhibitor (Gö6983) confirmed this result. Furthermore, a higher concentration of the Gö6983 inhibitor significantly reduced levels of PKC in caveolin-1-enriched fractions following EHEC O157:H7 challenge; these findings also suggest that bacterial challenge activates an atypical isoform of PKC (45). The effects of the pharmacological inhibitors were complemented and confirmed when we used a highly specific myristolated PKC pseudosubstrate.…”

Thymosin α₁ Activates Complement Receptor-Mediated Phagocytosis in Human Monocyte-Derived Macrophages

“…Thus, activation of different phagocytic receptors might not only be dependent sensu strictiori on the type of ligand or activator molecule, but also on the ‘activation state' of the host cell, which in turn is dependent both on its level of differentiation and on the experimental conditions of testing. This might also explain the differences in the expression of the proinflammatory cytokine genes found by us in mature macrophages from peripheral blood, and those reported by others in bone marrow-derived macrophages following Tα1 treatment [29]. …”

“…In addition, Tα1 upregulates the expression of Toll-like receptors (TLRs) 2, 5, 8 and 9 in murine DCs and protects mice from challenge by invasive aspergillosis in the MyD88 (myeloid differentiate factor 88)-dependent way [28]. Tα1 is capable of activating a TRAF6-atypical protein kinase C (PKC)-IκB kinase signaling pathway that leads to the activation of nuclear factor-κB, which in turn initiates cytokine gene expression in murine bone marrow-derived macrophages [29]. These studies provide relevant insights into how Tα1 exerts its immunomodulatory activity, but additional research is needed for a complete comprehension of the mechanism(s) involved in the Tα1-cell interaction.…”

Immunotherapy for hepatitis B in the direct acting antiviral era: Reevaluating the thymosin α1 efficacy trials in the light of a combination therapy approach

“…Thymosin alpha 1 (Tα1, thymalfasin, Zadaxin) is a peptide biologic with immunomodulatory activities and therapeutic applicability in several diseases including primary immunodeficiency diseases, depressed response to vaccination, CHB and cancer . To date, over 3000 patients have received Tα1 with minimal toxicity and significant benefit.…”