Analysis of apoptosis induction and NF-κB activation mediated by death receptors

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Santonin-related compounds (SRCs) were synthesized from the starting material L-α-santonin and tested for the biological activity on the expression of ICAM-1 in response to stimulation with the inflammatory cytokine IL-1. SRC2, one of the bromoketone derivatives, devoid of α-methylene-γ-lactone strongly inhibited the IL-1-induced ICAM-1 expression. The nuclear translocation of NF-κB and the IκB degradation were prevented by SRC2, suggesting that SRC2 blocks the IL-1 signaling pathway upstream of the IκB degradation. A close structural analogue of cycloheximide, E-73 (acetoxycycloheximide) was found to specifically inhibit TNF-induced ICAM-1 expression. The nuclear translocation of NF-κB as well as the IκB degradation induced by TNF, but not IL-1, were markedly prevented by E-73. Activation of p38 MAP kinase seems to be involved in the inhibitory effect of E-73 on the TNF-induced NF-κB activation.The mycotoxin penicillic acid inhibited apoptosis induced by Fas ligand. Penicillic acid significantly blocked self-cleavage of caspase-8 in the DISC, although it did not influence Fas ligand-induced DISC formation. In the cell-free system, cytochrome C-induced caspase-9 activation was inhibited by penicillic acid, although the toxin did not inhibit activated caspase-3. Thus, penicillic acid seems to target iniciator caspases such as caspase-8 and -9 by preventing their self-cleavage.Under conditions in which proliferation of CD3-activated human peripheral T lymphocytes is increased by recombinant Fas ligand, there was activation of the transcription factor NF-κB and AP-1 and recruitment of the caspase-8 inhibitor FLIP into the DISC.FLIP interacted with the adaptor proteins TRAF-1, TRAF-2, the kinase RIP, MAKKK Raf-1, resulting in the activation of NF-κB and Erk signaling pathways. In T cells FLIP seems to act cooperatively with stimulation through T cell receptors and thereby augment NF-κB and Erk activation, leading to increased production of IL-2.