p53-dependent radiation-induced crypt intestinal epithelial cells apoptosis is mediated in part through TNF-TNFR1 system

Abstract

Radiation induces apoptosis of crypt intestinal epithelial cells (IEC) through a pathway that is largely dependent on p53. However, exactly how p53 mediates IEC apoptosis is unclear. Studies in vitro suggest that one mechanism by which p53 mediates apoptosis is through its ability to transactivate members of the TNF receptor family of`Death Receptors'. Here, we examined the role of one of its member, TNF receptor type 1 (TNFR1), in an in vivo model of p53-dependent radiation-induced IEC apoptosis. We demonstrate that mice genetically engineered to be de®cient in TNF receptor type 1 (TNFR1 7/7) and mice injected with TNFR1-fusion chimeric protein (TNFR1-Fc; a competitive inhibitor of TNFR1) were partially protected (30 ± 40%) from p53-dependent radiation-induced IEC apoptosis. However, we found no evidence to support the possibility p53 transcriptionally regulates the expression of TNFR1 nor increases the susceptibility of IEC to TNF-mediated apoptosis. Interestingly, we found that injection of TNF readily induced IEC apoptosis and that radiation induced a p53-dependent increase in the intestinal level of TNF. Furthermore, injection of a neutralizing anti-TNF mAb reduced p53-dependent radiation-induced IEC apoptosis by approximately 60%. Overall, these results suggest that p53-dependent radiation-induced IEC apoptosis is mediated in part through ability of p53 to regulate TNF, which subsequently induces IEC apoptosis through TNFR1. Oncogene (2001) 20, 812 ± 818.

Tumor Necrosis Factor α Up-regulates Non-lymphoid Fas-ligand following Superantigen-induced Peripheral Lymphocyte Activation

“…We performed RNase protection assays on primary IEC and found constitutive expression of TNFR1 (p55) (Fig. 1C), consistent with a previous observation of TNFR1 protein on the surface of IEC (19). Because TNF␣ is produced by activated lymphocytes infiltrating the small intestine (20), we investigated the possibility that TNF␣ acts through the TNFR1 on IEC to induce Fas-ligand in IEC following SEB-induced activation of peripheral lymphocytes.…”

“…5). IEC express TNFR1 (19), and animals lacking TNFR1 are similarly resistant to induction of IEC Fas-ligand expression following SEB injection.…”

Intestinal Epithelial Apoptosis Initiates Gross Bowel Necrosis in an Experimental Rat Model of Neonatal Necrotizing Enterocolitis

“…Key factors in NEC pathogenesis, such as hypoxia reoxygenation, PAF, TNF-␣, and endotoxin, have been shown to increase mucosal permeability (17)(18)(19)(20)(21). Most of these mediators have been shown to cause apoptosis of intestinal epithelial cells as well (22)(23)(24), but the connection between apoptosis and subsequent gross morphologic damage in NEC is yet to be elucidated.…”

The Role of p53 and Fas in a Model of Acute Murine Graft-versus-Host Disease

“…Hence, it is possible that sublethal irradiation may enhance the effect of GVHD through its effect on host APC, a population that is relatively resistant to radiationinduced apoptosis. We have shown that sublethal radiation induces the systemic production of numerous proinflammatory cytokines such as TNF (40), which is primarily produced by APC, and this induction is attenuated in the p53 Ϫ/Ϫ mice. Hence, it is plausible that radiation induces an initial critical inflammatory response through its effect on p53, and this is further propagated by the injection of parental cells recognizing alloantigen in a concept commonly regarded as cytokine storm (41).…”