Radiation-induced bystander and abscopal effects, in which DNA damage is produced by inter-cellular communication, indicate mechanisms of generating damage in addition to those observed in directly irradiated cells. In this article, we show that the bone marrow of irradiated p53+/+ mice, but not p53–/– mice, produces the inflammatory pro-apoptotic cytokines FasL and TNF-α able to induce p53-independent apoptosis in vitro in nonirradiated p53–/– bone marrow cells. Using a congenic sex-mismatch bone marrow transplantation protocol to generate chimeric mice, p53–/– hemopoietic cells functioning in a p53+/+ bone marrow stromal microenvironment exhibited greater cell killing after irradiation than p53–/– hemopoietic cells in a p53–/– microenvironment. Cytogenetic analysis demonstrated fewer damaged p53–/– cells in a p53+/+ microenvironment than p53–/– cells in a p53–/– microenvironment. Using the two different model systems, the findings implicate inflammatory tissue processes induced as a consequence of p53-dependent cellular responses to the initial radiation damage, producing cytokines that subsequently induce ongoing p53-independent apoptosis. As inactivation of the p53 tumor suppressor pathway is a common event in malignant cells developing in a stromal microenvironment that has normal p53 function, the signaling processes identified in the current investigations have potential implications for disease pathogenesis and therapy.

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