Prothymosin Alpha and Immune Responses

Abstract

The thymus gland produces soluble molecules, which mediate significant immune functions. The first biologically active thymic extract was thymosin fraction V, the fractionation of which led to the isolation of a series of immunoactive polypeptides, including prothymosin alpha (proTα). ProTα displays a dual role, intracellularly as a survival and proliferation mediator and extracellularly as a biological response modifier. Accordingly, inside the cell, proTα is implicated in crucial intracellular circuits and may serve as a surrogate tumor biomarker, but when found outside the cell, it could be used as a therapeutic agent for treating immune system deficiencies. In fact, proTα possesses pleiotropic adjuvant activity and a series of immunomodulatory effects (eg, anticancer, antiviral, neuroprotective, cardioprotective). Moreover, several reports suggest that the variable activity of proTα might be exerted through different parts of the molecule. We first reported that the main immunoactive region of proTα is the carboxy-terminal decapeptide proTα(100-109). In conjunction with data from others, we also revealed that proTα and proTα(100-109) signal through Toll-like receptor 4. Although their precise molecular mechanism of action is yet not fully elucidated, proTα and proTα(100-109) are viewed as candidate adjuvants for cancer immunotherapy. Here, we present a historical overview on the discovery and isolation of thymosins with emphasis on proTα and data on some immune-related new activities of the polypeptide and smaller immunostimulatory peptides thereof. Finally, we propose a compiled scenario on proTα's mode of action, which could eventually contribute to its clinical application.

Antitumor Reactive T-Cell Responses Are Enhanced In Vivo by DAMP Prothymosin Alpha and Its C-Terminal Decapeptide

“…Moreover, total spleen cells isolated from mice treated with proTα/AWE and proTα(100–109)/AWE efficiently killed autologous B16.F1- and NK/LAK-sensitive targets, a result verifying the in vivo generation of functionally competent antimelanoma-reactive T and NK effectors. This finding is in agreement with a series of reports showing that proTα and proTα(100–109) enhance the in vitro and in vivo cytotoxicity of both MHC- and non-MHC-restricted effector cells (T and NK/LAK cells, respectively) and this effect is IL-2-dependent (reviewed in [5,52]). Thus, we next assessed whether melanoma T-cell invasion and cytotoxic responses were sustained by a favorable cytokine profile, in this case, of the Th1-type.…”

Acute Thymic Involution and Mechanisms for Recovery

“…It is considered a primary immune organ in jawed vertebrates, in which it plays important roles in the selection, proliferation, development and differentiation of T cells and provides protection against infections by various pathogens (Bajoghli and Guo 2011;Gameiro et al 2010;Liu et al 2014). Despite its significance in immunity (Miller 2002;Samara et al 2016), the shrinkage of thymus that occurs with aging results in a decrease in tissue mass along with architectural alterations. In general, almost all vertebrates that possess a thymus experience this ancient and conserved evolutionary process, termed age-related thymic involution (Shanley et al 2009), although the thyme of some shark species are reported not to undergo involution (Zakharova 2009).…”

Ecto-F0/F1 ATPase as a novel candidate of prothymosin α receptor

“…ProTα is generally thought to be an oncoprotein that is correlated with cell proliferation by sequestering anti-coactivator factor, a repressor of estrogen receptor activity, in various cells. In view of the history of discovery, a lot of immune-related studies on ProTα have been reported [2,3,4]. Independently, we have first identified ProTα from the conditioned medium of primary culture of cortical neurons as an anti-necrosis factor [5].…”