TNF-induced enterocyte apoptosis in mice is mediated by the TNF receptor 1 and does not require p53

Abstract

Injection of recombinant mouse TNF into mice is known to induce a shrinkage of the duode-nal villi, which becomes evident 30-90 min later and is associated with a detachment of enterocytes in the lumen. These cells can be collected by lavage and are all apoptotic, i.e. hypodiploid as seen by flow cytometric analysis. Thus the count of detached cells was used as an evaluation of the TNF-induced cell loss and apoptosis in the mucosa. TNF injection induced a cell loss of similar magnitude in wild-type (+/+) or in mice lacking the TNF receptor (TNFR)2 (p75, TNFR2 −/−), while mice lacking the TNFR1 (p55, TNFR1 −/−) were completely resistant to this effect. TNF increased the expression of p53 tumor suppressor gene in the enterocytes from the crypts but not from the villi, as seen by Western blots and histochemis-try. TNF increased the expression of p53 in both TNFR2 −/− and TNFR1 −/− mice. Furthermore , enterocyte cell loss was not attenuated in p53 −/− mice. The results indicate that TNF, acting on its receptor 1, induces an apoptotic detachment of the enterocytes from the tip of the villi (i.e. the old enterocytes), while in the enterocytes from the crypts (the young entero-cytes) TNF increases, via either TNFR1 or TNFR2, the expression of p53, without inducing apoptosis.

Peptide vaccination of mice immune to LCMV or vaccinia virus causes serious CD8+ T cell-mediated, TNF-dependent immunopathology

“…However, mice that express mTNF, but not sTNF, show markedly increased resistance to LPS-induced shock (40), implicating sTNF in that shock paradigm, and this, together with the extremely high levels of sTNF observed after peptide injection ( Figure 5A), leads us to view sTNF as the main suspect. The data in Figures 6 and 8 show that enterocyte apoptosis and host death are both mediated by TNF, and the experiments with zVADfmk (Figures 8 and 9) suggest that both effects are caspase-dependent, consistent with the previous reports from other laboratories (22,41). We believe it likely that the 2 effects are related: extensive apoptosis of enterocytes (and, possibly, of other somatic cells) may be lethal.…”

Hydroxylase Inhibition Abrogates TNF-α–Induced Intestinal Epithelial Damage by Hypoxia-Inducible Factor-1–Dependent Repression of FADD

“…injection of murine rTNF-a (10 mg in 200 ml saline; BioLegend, San Diego, CA) was administered to induce acute enteropathy, characterized by massive apoptosis of the enterocytes, as previously reported (23)(24)(25). Control animals (n = 2) received i.v.…”

Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

“…22,23) and of inflammatory mediators, such as IL-17, IL-1, IFN-β, ROS, and iNOS (24)(25)(26)(27)(28). Multiple organs, such as intestine, liver, and kidney, suffer from the TNF-induced effects, but it is still unclear which cell type is essential in mediating/initiating the TNF-induced toxicity (2,29,30). Of interest, several acute inflammatory conditions in which TNF plays a role have been attributed to effects on the intestinal epithelial cells (IECs) (31,32).…”