The 10th Euroconference of the European Cell Death Organization (ECDO), coorganized with the Pasteur Institute and the Institut Gustave Roussy, took place in Paris from October 11–13, 2002. One leitmotif of this conference was the debate to which extent cell death depends on the activation of caspases.
In his impressive keynote lecture, Peter Krammer informed the audience that the European Commission decided that Cell Death would not be a prioritized area of research in Europe during the next 4 years, a fact that–although met by general incredulity–may determine Europe's decadence in yet another key area of biomedical research. Peter Krammer insisted on the role of death receptors in a model of murine stroke, in which the simultaneous activation of the CD95/CD95 ligand system (by the gld mutation) and the TNF/TNF-receptor system (by knockout of the tnf gene) has a major positive effect on animal survival and health, involving either a cell-autonomous effect on neuronal cell survival or a reduction of deleterious lymphoid infiltration into the partially damaged brain areas. In septic patients, both the spontaneous and the TAR-triggered apoptosis of circulating T lymphocytes were found to be strongly increased, and this death was found to be caspase-independent, ex vivo. In strict contrast, Don Nicholson reported that caspase inhibition by newly developed caspase inhibitors may have a major life-preserving effect in an animal model of septic shock, a finding that suggests that the proinflammatory function and/or the proapoptotic function of caspases may have a major role in the pathogenesis of the cytokine overproduction syndrome leading to massive cell death of immune, endothelial and epithelial cells in sepsis. Don Nicholson insisted on the observation that caspase inhibitors have differential half-effective doses on distinct apoptosis characteristics such as the cleavage of defined caspase substrates and DNA degradation, implying that very high doses of caspase inhibitors must be used to justify the conclusion that cell death is caspase-independent. He also presented sequence data on the human caspase-12 gene, indicating that, at least in Caucasians, this gene is inactivated because of a Stop mutation. He concluded that caspase-12 cannot have the same function as a sensor for ER stress and neuronal damage in the human system as in the murine system. This interpretation was contested by Junjin Yuan, who suggested that the true functional human caspase-12 remains to be discovered. Don Nicholson showed that several caspase cleavage products, including caspase-digested XIAP and β-amyloid, exhibit structural similarity with the N-terminus of Smac/DIABLO and may neutralize caspase-inhibitory IAPs, thereby deinhibiting and accelerating caspase activation. In some cases, activation of noncaspase proteases may be important for the stimulation of the caspase cascade, as reported by Hans-Uwe Simon, who showed that, in neutrophil granulocytes, calpain-1 activation may be critical for the activation of Bax, mitochondrial permeabilization, and consequent caspase activation.
