Caspase-8 is the prototypical apoptosis initiator Caspase downstream of TNF super- family death receptors. With substrates that include apoptosis-related effector Caspases and pro-apoptotic Bcl-2 family members, active Caspase-8 is capable of unleashing cascades of cellular events that result in apoptosis.1 Indeed, Caspase-8-deficient cells are resistant to death receptor-mediated cell death both in vitro and in vivo.2-4 While recent knockout studies support the role of Caspase-8 in apoptosis, they also reveal several other putative functions (Figure 1).
|Figure 1. Knockouts suggest both apoptosis-related and apoptosis-independent roles for Caspase-8. Caspase-8-deficient cells are insensitive to death receptor ligand-induced apoptosis. The embryonic lethal phenotype observed is likely due to degeneration of the extra-embryonic yolk sac vasculature and abnormal cardiac development. Knockouts in cells of the hematopoietic lineage reveal putative roles for Caspase-8 in lymphoid and myeloid development, the proliferation and activation of T cells, and the ability to generate an effective anti-viral immune response.|
Caspase-8 knockout is embryonic lethal at approximately day 11.5.3 The first abnormality, observed at approximately day 10.5, is a regression of the extra-embryonic yolk sac vasculature followed by abdominal hemorrhage due to cardiac rupture.3,5 Apoptosis is observed in cells surrounding the yolk sac vessels and in the cardiac myocytes themselves.4,6 Also accompanying Caspase-8 knockout are defects in neural tube morphogenesis.5 Interestingly, cardiac tissue and neural tube abnormalities are rescued by ex vivo culture, suggesting that the Caspase-8-/- phenotype is not intrinsic to these tissues specifically.5 These phenotypes may be due to Caspase-8 deficiency in endothelial cells or their precursors. When Caspase-8 is targeted for knockout in endothelial cells using a Cre/loxP recombination system (Tie-1/Cre), transgenic mice exhibit cardiovascular, neural tube, and embryonic lethal phenotypes similar to the full knockout.4
Certain aspects of lymphoid cell development and activity appear to be affected by Caspase-8 knockout. For instance, Caspase-8-deficient bone marrow (BM) hematopoietic progenitors are unable to repopulate B cells and T cells in the BM and lymphoid organs of sub-lethally irradiated mice.4 When Caspase-8 is knocked out in the T cell lineage using Cre/loxP recombination (Lck/Cre), transgenic mice are viable, but appear to have deficiencies in both T cell expansion and activation.6 Caspase-8 deletion might also affect T cell development at early stages of differentiation, but its role may decrease in importance as the cells mature to, and beyond, the late double negative stage.4,6 In addition, Lck/Cre transgenic mice are unable to develop an effective immune response to viral infection.6 Caspase-8 may have a role in myeloid development as well. When Caspase-8 knockout is targeted to the myeloid lineage using Cre/loxP recombination (LysM/Cre), myeloid progenitors do not differentiate into macrophages in response to M-CSF treatment.4
Recent knockout studies appear to reveal several potential roles for Caspase-8 that are independent of apoptosis. In fact, apoptosis appears to be a consequence of Caspase-8 knockout in several instances suggesting a pro-survival function.4,5 Caspase-8 knockouts exhibit deficiencies in leukocyte differentiation, proliferation, and the immune response further indicating Caspase-8 may be a multifunctional enzyme.4,6 The mechanisms underlying these activities are poorly understood. It will be of interest to monitor future studies that identify thesubstrates involved, and further define the role of Caspase-8 in both apoptosis and in apoptosis-independent activities.