Prothymosin Alpha: An Alarmin and More...

Background/Objective: Prothymosin alpha (proT alpha) is a ubiquitous polypeptide first isolated by Haritos in 1984, whose role still remains partly elusive. We know that proT alpha acts both, intracellularly, as an anti-apoptotic and proliferation mediator, and extracellularly, as a biologic response modifier mediating immune responses similarly to molecules termed as "alarmins". Our research team pioneered the elucidation of the mechanisms underlying the observed activities of proT alpha. Results: We were the first to demonstrate that proT alpha levels increase during normal and abnormal cell proliferation. We showed that proT alpha acts pleiotropically, inducing immunomodulatory effects on immune cell populations. We revealed that the immunoreactive region of proT alpha is the carboxyterminal decapeptide proT alpha(100-109) and both molecules stimulate innate immune responses, signaling through Toll-like receptors (TLRs), specifically TLR-4. We reported that proT alpha and proT alpha(100-109) bind on the surface of human neutrophils on sites involving TLR-4, and cell activation is complemented by cytoplasmic calcium ion influx. Further, we showed that proT alpha and proT alpha(100-109) act as adjuvants upstream of lymphocyte stimulation and, in the presence of antigen, promote the expansion of antigen-reactive effectors. Most recently, we reported that proT alpha(100-109) may accumulate in experimentally inflamed sites and can serve as a surrogate biomarker in severe bacterial infections, proposing that extracellular release of proT alpha or proT alpha(100109) alerts the immune system during conditions of danger. Conclusion: We, therefore, suggest that proT alpha, and likely proT alpha(100-109), act as alarmins, being important immune mediators as well as biomarkers, and could eventually become targets for new therapeutic/diagnostic approaches in immune-related diseases like cancer, inflammation, and sepsis.