Tumor necrosis factor-á (TNF-á) is a multifunctional
cytokine involved in host defense,
inflammation,
apoptosis,
autoimmunity,
organogenesis and lymphoid microarchitecture. Many of these activities may be explained by the
ability of this
cytokine to induce distinct
signal transduction pathways that recruit regulatory
proteins involved in
differentiation, cell death or
cell proliferation. In this
review, we discuss the contribution of
caspases -3, -6, -7 and -8, and of
cyclin-dependent kinases (CDKs),
cyclin B and
cyclin-dependent kinase inhibitors (CKI p21 and p27), as well as
retinoblastoma tumor suppressor in the signaling cascades triggered by TNF-á to induce
apoptosis,
necrosis and
cellular proliferation in the murine
cell lines NIH3T3 and WEHI-164 and the
human cervical
carcinoma cell line HeLa-S3. Based on the findings of many
literature reports and our own data, we discussed a model in which
caspases are continuously activated throughout the
cell cycle and kept at a critical threshold level by IAP (inhibitor of
apoptosis) antagonists. Following the release of Smac/Diablo and HtrA2/OMI from
mitochondria in response to diverse stimuli, this threshold is overcome and results in amplified
caspase activation and
cell death. An alternative,
caspase-independent mechanism of
cell death is induced in NIH3T3 fi broblasts by a combination of TNF and the pan-
caspase inhibitor z-VADfmk. This
cell death phenotype, known as
necroptosis, displays some morphological features of
apoptosis and
necrosis. Although
caspases are critical regulators of the TNF signaling pathway during cellular
life and
death, the mechanisms involved in the fine
regulation of their dual effects remain to be fully elucidated.