Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death

AC LIBERMAN; D REFOJO; M ANTUNICA-NOGUEROL; F HOLSBOER; E ARZT

MOLECULAR IMMUNOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2011 p. 1234 - 1238

0161-5890

Glucocorticoids (GC) and cAMP-dependent signaling pathways exert diverse and relevantimmune regulatory functions, including a tight control of T cell death and homeostasis. Both of these signaling molecules inhibit TCR-induced cell death and FasL expression, but theunderlying mechanisms are still poorly understood. Therefore, to address this question, weperformed a comprehensive screening of signaling pathways downstream of the TCR, in order to define which of them are targets of cAMP- and GCmediatedinhibition. We found that cAMP inhibited NF-kB and ERK pathways through a PKA-dependent mechanism, whileDexamethasone blocked TCR-induced NF-kB signaling. Although GCs and cAMP inhibited the induction of endogenous FasL mRNA expression triggered by TCR activation, they potentiated TCR-mediated induction of FasL promoter activity in transient transfection assays. However, when the same FasL promoter was stably transfected, the facilitatory effect of GCs and cAMP became inhibitory, thus resembling the effects on endogenous FasL mRNA expression. Hence, the endogenous chromatinizationstatus known to occur in integrated or genomic vs episomic DNA might be critical for proper regulation of FasL expression by cAMP and GCs. Our results suggest that the chromatinization status of the FasL promoter may function as a molecular switch, controlling cAMP and GC responsiveness and explaining why these agents inhibit FasL expression in T cells but induce FasL in other cell types.