Mechanism of thymocyte apoptosis induced by serum of tumor-bearing host: the molecular events involved and their inhibition by thymosin alpha-1

The observations presented in this paper indicate that serum of Dalton's ly mphoma (DL) bearing mice contained certain soluble factor(s) that augmented the induction of apoptosis in thymocytes in a time- and dose-dependent man ner. DL-ascitic fluid and DL-conditioned medium could also induce apoptosis of thymocytes in vitro, though the magnitude of the same was consistently lower than that induced by serum of DL-bearing mice. It was observed that t he interaction of FasL, and TNF alpha with their respective receptors could trigger apoptosis in thymocytes. Elucidation of the signal transduction me chanism revealed involvement of protein tyrosine kinase, protein kinase C a nd ser/thr phosphatases with concomitant increase in the level of protein p roducts of apoptosis associated genes p53, bax, bad, fas and fas ligand and cleavage of N-terminal 23 kDa fragment of Bcl-2 that exhibited Bar-like de ath effector properties. Further, we report, for the first time, the abilit y of thymosin alpha-1, an immunopotentiating thymic hormone, to antagonize apoptosis in thymocytes induced by factors present in serum of DL-bearing m ice. The underlying mechanism of tumor serum induced apoptosis inhibition b y thymosin alpha-1 was also analyzed. The signal transduction cascade evoke d by thymosin alpha-1 involves activation of protein kinase C with a decrea se in the level of protein products of proapoptotic genes like bax and bad and increase in the protein products of bcl-2 gene. (C) 2000 International Society for Immunopharmacology. Published by Elsevier Science Ltd. All righ ts reserved.