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.

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Current evidence suggests that increased expression of Th1-associated cytokines is important for immune-mediated eradication of hepatitis C infection, while an increase in Th2-associated cytokines is associated with persistence of infection. In this study we evaluated the effects of thymosin-alpha1 (TA1), a naturally occurring thymic peptide, and interferon-alpha (IFN-alpha) on cytokine production in peripheral blood mononuclear cells from untreated patients with chronic hepatitis C. We examined the effect of incubation with TA1, IFN-alpha, or both, on production of Th1-associated cytokines (IL-2, IFN-gamma), Th2-associated cytokines (IL-4, IL-10), and synthesis of the antiviral protein 2',5'-oligoadenylate synthetase. TA1 treatment induced a significant increase in production of IL-2 and 2',5'-oligoadenylate synthetase. Smaller increases were also seen after treatment with IFN-alpha, while incubation with TA1 and IFN-alpha together led to an additive or synergistic effect. Incubation with TA1 resulted in a decrease in IL-4 and IL-10, whereas IFN-alpha increased these cytokines. The addition of TA1 to IFN-alpha significantly reversed this IFN-alpha-induced increase. Hence, TA1 treatment could benefit patients with hepatitis C infection by increasing the Th1-type response, fundamental for sustained clearance of hepatitis C; and by decreasing the Th2-type response, associated with persistence of viraemia.

Thymosin alpha 1, originally isolated as the compound responsible for reconstitution of immune function in thymectomized animal models, has enjoyed a wide-ranging clinical development program over the past decades, extending across multiple companies, indications, countries, and continents. This paper provides an overview of this complex picture. The extensive clinical studies began with small studies conducted with an impure mixture of peptides under the aegis of physician-sponsored INDs submitted to the US FDA, in subjects with primary immune deficiency such as DiGeorge syndrome. Subsequent studies ranged all the way to large phase-3 trials conducted with synthetically produced thymosin alpha 1 and hundreds of patients, in many countries including the United States, Italy, and China.

800 MHz NMR structure of the 28-residue peptide thymosin alpha-1 in 40% TFE/60% water (v/v) has been determined. Restrained molecular dynamic simulations with an explicit solvent box containing 40% TFE/60% TIP3P water (v/v) were used, in order to get the 3D model of the NMR structure. We found that the peptide adopts a structured conformation having two stable regions: an alpha-helix region from residues 14 to 26 and two double β-turns in the N-terminal twelve residues which form a distorted helical structure.