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1 Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
* To whom correspondence should be addressed. E-mail: WSTENSON{at}im.wustl.edu.
Lipopolysaccharide (LPS) is radioprotective in the mouse small intestine through a mechanism that includes the synthesis of cyclooxygenase-2 (Cox-2) and prostaglandin
(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 RAG-1 -/- mice. Mice were given parenteral LPS and then subjected to 12 Gy total body 
-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 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 defines 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.
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