p53 Mediates TNF-Induced Epithelial Cell Apoptosis in IBD

Abstract

Chronic ulcerative colitis (CUC) is characterized by increased intestinal epithelial cell (IEC) apoptosis associated with elevated tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS), and p53. We previously showed that p53 is increased in crypt IECs in human colitis and is needed for IEC apoptosis in chronic dextran sulfate sodium-colitis. Herein, we examined the roles of TNF and iNOS in regulating p53-induced IEC apoptosis in CUC. The IEC TUNEL staining, caspases 3, 8, and 9, and p53 protein levels, induced by anti-CD3 monoclonal antibody (mAb) activation of T cells, were markedly reduced in TNF receptor 1 and 2 gene knockout mice. Induction of IEC apoptosis correlated with increased p53, which was attenuated in iNOS(-/-) mice. IEC p53 levels and apoptosis were reduced in IL-10(-/-) colitic mice treated with neutralizing TNF mAb and the iNOS inhibitor, aminoguanidine, further suggesting that TNF and iNOS are upstream of p53 during colitis-induced IEC apoptosis. IEC apoptosis and p53 levels were assessed in control versus untreated or anti-TNF-treated CUC patients with equivalent levels of inflammation. Data indicated that IEC apoptosis and p53 levels were clearly higher in untreated CUC but markedly reduced in patients treated with anti-TNF mAb. Therefore, TNF-induced iNOS activates a p53-dependent pathway of IEC apoptosis in CUC. The inhibition of IEC apoptosis may be an important mechanism for mucosal healing in anti-TNF-treated CUC patients.

The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

“…However, NOD2 ΔLyz2 mice showed higher numbers of epithelial apoptotic bodies and increased expression of TNF-a and IL-22 compared with WT mice. TNF-a plays a crucial role in the pathogenesis of CD and high levels of TNF-a can alter intestinal epithelial barrier integrity (42)(43)(44). Chronic stimulation of Nod2 in human monocyte-derived macrophages has been associated with a downregulation of TNF-a secretion (45), indicating that expression of Nod2 is important for both the induction and the regulation of this response.…”

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

“…This anti-TNF therapy promotes mucosal healing, and is associated with reduced epithelial apoptosis. 32 We showed that TUDCA is able to dose-dependently inhibit TNF-induced caspase-3 activation in colonocytes during co-incubation. Moreover, preincubation of HT29 cells with TUDCA still resulted in reduced caspase-3 activation following TNF stimulation, albeit to a much lesser extent.…”

Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD

“…29,30 Moreover, TNF is generally a prominent inducer of cell death in the intestinal epithelium. [31][32][33][34][35] Against the background of the increased expression of TNF in the gut after allo-HCT ( Figure 2C) and the established strong ability of the TWEAK/Fn14 system to enhance TNFR1-induced cell death, [36][37][38] we addressed the possibility that 18D1-dead affects intestinal apoptosis after allo-HCT. Immunohistochemical evaluation of the GI tract of control hIgG1 and 18D1-dead treated mice revealed a significant reduction in the number of cleaved PARP1-positive cells within the small bowel ( Figure 3A).…”