Abstracts (complete list) - Wissenschaft Online

Marc A. Blank, Olaf Utermohlen, Holger M. Reichardt, Marco J. Herold
Dissecting the apoptotic pathways induced by Glucocorticoids
in T-cells
Glucocorticoids (GC) induce apoptosis in many cell types, but the mechanisms are not
well understood. Recently it was reported that the proapoptotic Bcl-2 family member
Bim and an upregulation of ceramides by a caspase-activated acidic sphingomye- linase
(aSMase) play important roles. In order to study their involvement in GC- induced
apoptosis we took advantage of the GC-sensitive murine T-cell lymphoma line WEHI
7.15a. Overexpression of retrovirally expressed shRNAs against Bim or aSMase had no
influence, whereas knockdown of the GC receptor (GR) itself rendered these cells
resistant to Dexamethasone. In addition, various pharmacological inhibitors of ceramide
production had no influence on GC-induced apoptosis. Moreover, thymocytes and
peripheral T-cells from aSMase knockout mice were equally sensitive to GC induced
apoptosis as wildtype cells. Furthermore, we confirmed the in vitro knock down results
of Bim and the GR by introducing shRNAs into hematopoietic stem cells that were used
to reconstitute lethally irradiated mice. While Bim inactivation did not impact ex vivo GCinduced
apoptosis, loss of GR expression prevented cell death. Therefore we conclude
that the involvement of Bim and aSMase is negligible in GC-induced apoptosis of T-cells.