CRYPT STEM-CELL SURVIVAL IN THE MOUSE INTESTINAL EPITHELIUM IS REGULATED BY PROSTAGLANDINS SYNTHESIZED THROUGH CYCLOOXYGENASE-1

Prostaglandins (PGs) are important mediators of epithelial integrity a nd function in the gastrointestinal tract. Relatively little is known, however, about the mechanism by which PGs affect stem cells in the in testine during normal epithelial turnover, or during wound repair. PGs are synthesized from arachidonate by either of two cyclooxygenases, c yclooxygenase-1 (Cox-1) or cyclooxygenase-2 (Cox-2), which are present in a wide variety of mamalian cells. Cox-1 is thought to be a constit utively expressed enzyme, and the expression of Cox-2 is inducible by cytokines or other stimuli in a variety of cell types. We investigated the role of PGs in mouse intestinal stem cell survival and proliferat ion following radiation injury. The number of surviving crypt stem cel ls was determined 3.5 d after irradiation by the microcolony assay. Ra diation injury induced a dose-dependent decrease in the number of surv iving crypts. Indomethacin, an inhibitor of Cox-1 and Cox-2 further re duced the number of surviving crypts in irradiated mice, The indometha cin dose response for inhibition of PGE(2) production and reduction of crypt survival were similar. Dimethyl PGE(2) reversed the indomethaci n-induced decrease in crypt survival. Selective Cox-2 inhibitors had n o effect on crypt survival. PGE(2), Cox-1 mRNA, and Cox-1 protein leve ls all increase in the 3 d after irradiation. Immunohistochemistry for Cox-1 demonstrated localization in epithelial cells of the crypt in t he unirradiated mouse, and in the regenerating crypt epithelium in the irradiated mouse. We conclude that radiation injury results in increa sed Cox-1 levels in crypt stem cells and their progeny, and that PGE(2 ) produced through Cox-1 promotes crypt stem cell survival and prolife ration.