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MUCOSAL BIOLOGY

TNFR1 mediates the radioprotective effects of lipopolysaccharide in the mouse intestine

¹Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri 63110; and ²Department of Pathology, University of Alabama, Birmingham, Alabama 35294

Submitted 20 December 2002 ; accepted in final form 18 September 2003

LPS is radioprotective in the mouse small intestine through a mechanism that includes the synthesis of cyclooxygenase-2 (COX-2) and PGE₂. The goal of this study was to identify the intermediate steps in this process. We used wild-type (WT) C57BL/6 mice and knockouts for tumor necrosis factor receptors 1 and 2 (TNFR1^-/-, TNFR2^-/-) and recombination-activating gene 1^-/- mice. Mice were given parenteral LPS and then subjected to 12 Gy total body gamma irradiation. The number of surviving intestinal crypts was assessed 3.5 days after irradiation using a clonogenic assay. Crypt cell apoptosis was assessed by histology. Parenteral administration of LPS induced COX-2 expression, PGE₂ production, and radioprotection in WT and TNFR2^-/- mice but not in TNFR1^-/- mice. TNFR1^-/- mice were radioprotected by administration of exogenous 16,16-dimethyl PGE₂. Immunohistochemical studies localized TNFR1 and COX-2 expression to subeptihelial fibroblasts and villus epithelial cells. Radiation-induced apoptosis was reduced by pretreatment with LPS in WT and TNFR2^-/- mice but not in TNFR1^-/- mice. In the absence of LPS, crypt survival was elevated in TNFR1^-/- when compared with WT mice. These findings demonstrate that TNFR1 function is required for LPS-induced radioprotection in C57BL/6 mice and define an essential role for TNFR1 function in the induction of COX-2 expression and PGE₂ production in this process. The immunolocalization of TNFR1 and COX-2 expression to subepithelial fibroblasts following LPS administration suggests that this cell type plays an intermediate role in LPS-induced radioprotection in the intestine.

cyclooxygenase; prostaglandin E₂; gamma radiation; epithelial cell; subepithelial fibroblast

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