TNF-INDUCED ENTEROCYTE APOPTOSIS IN MICE IS MEDIATED BY THE TNF RECEPTOR-1 AND DOES NOT REQUIRE P53

Injection of recombinant mouse TNF into mice is known to induce a shri nkage of the duodenal villi, which becomes evident 30-90 min later and is associated with a detachment of enterocytes in the lumen. These ce lls 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 comple tely resistant to this effect. TNF increased the expression of p53 tum or suppressor gene in the enterocytes from the crypts but not from the villi; as seen by Western blots and histochemistry. TNF increased the expression of p53 in both TNFR2 -/- and TNFR1 -/- mice. Furthermore, enterocyte cell loss was not attenuated in p53 -/- mice. The results i ndicate that TNF, acting on its receptor 1, induces an apoptotic detac hment of the enterocytes from the tip of the villi (i.e. the old enter ocytes), while in the enterocytes from the crypts (the young enterocyt es) TNF increases, via either TNFR1 or TNFR2, the expression of p53, w ithout: inducing apoptosis.