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Am J Physiol Gastrointest Liver Physiol (October 2, 2003). doi:10.1152/ajpgi.00537.2002
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Submitted on December 20, 2002
Accepted on September 23, 2003

Tumor Necrosis Factor Receptor 1 (TNFR1) Mediates the Radioprotective Effects of Lipopolysaccharide in the Mouse Intestine

Terrence E. Riehl1, Rodney D. Newberry1, Robin G. Lorenz1, and William F. Stenson1*

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 {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 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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