Figure 4. p55TNFR expression in the intestinal epithelium is a critical determinant for TNF-induced toxicity.

(A) Tnfrsf1a^+/–, Tnfrsf1a^+/flNeo, and Tnfrsf1a^+/flNeo mice with tissue-specific Cre expression were injected i.p. with 150 μg TNF, and lethality was monitored. (B) Relative intestinal permeability measured by increase in FITC signal in plasma of Tnfrsf1a^+/flNeo (gray) and Tnfrsf1a^+/flNeo IEC reactivation mice (black) orally gavaged with 4-kDa FITC-dextran and injected with TNF (0 hour, n = 3; 8 hours, n = 8). (C) IEC death in Tnfrsf1a^+/+, Tnfrsf1a^+/–, Tnfrsf1a^+/flNeo, and Villin-Cre⁺ Tnfrsf1a^+/flNeo mice 2 hours after TNF challenge (30 μg, i.p.). Similar amounts of TUNEL-positive cells on ileal sections were detected in all samples (n = 4–5; scale bar: 38 μm). Multiple time points (1, 4, and 8 hours after TNF) were tested, and all showed a similar amount of TUNEL-positive cells in Tnfrsf1a^+/+ and Tnfrsf1a^+/– IECs. (D) Tnfrsf1a^fl/fl (black line), Villin-Cre Tnfrsf1a^fl/+ (light gray line), and Villin-Cre Tnfrsf1a^fl/fl (dark gray line) mice were injected i.v. with 6 μg TNF, and lethality was monitored. (E) Relative intestinal permeability of Villin-Cre Tnfrsf1a^fl/+ mice compared with Tnfrsf1a^fl/+ mice when mice were injected with 7 μg TNF and orally gavaged with 4-kDa FITC-dextran (0 hours, n = 5; 8 hours, n = 11). (F) IEC death in Tnfrsf1a^–/–, Tnfrsf1a^+/fl, and Villin-Cre Tnfrsf1a^+/fl mice 2 hours after TNF challenge (6 μg, i.v.). Similar amounts of TUNEL-positive cells on ileal sections were detected in all samples (n = 6; scale bar: 38 μm). Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t test in B and E, and log-rank test in A and D).