p53-dependent and -independent pathways of apoptotic cell death in sepsis

Sepsis induces extensive apoptosis of lymphocytes, which may be responsible for the profound immune suppression of the disorder. Two potential pathway s of sepsis-induced lymphocyte apoptosis, Fas and p53, were investigated. L ymphocyte apoptosis was evaluated 20-22 h after sepsis by annexin V or DNA nick-end labeling. Pas receptor-deficient mice had no protection against se psis-induced apoptosis in thymocytes or splenocytes. p53 knockout mice (p53 (-/-)) had complete protection against thymocyte apoptosis but, surprisingl y, had no protection in splenocytes. p53(-/-) mice had no improvement in se psis survival compared with appropriately matched control mice with sepsis, We conclude that both p53-dependent and p53-independent pathways of cell d eath exist in sepsis, This differential apoptotic response of thymocytes vs splenocytes in p53(-/-) mice suggests that either the cellular response or the death-inducing signal is cell-type specific in sepsis, The fact that p 53(-/-) lymphocytes of an identical subtype (CD8(-)CD4(+)) were protected i n thymi but not in spleens indicates that cell susceptibility to apoptosis differs depending upon other unidentified factors.