We previously reported (Koji et al, J.Cell Biol. 125:1994) that the expression of keratinocyte growth factor (KGF) in the endometrium of the rhesus monkey was much higher in the luteal than the follicular phase, and that this increase was due to progesterone (P). Currently we are collaborating with J. Rubin's lab at NCI and are using mice to conduct pilot studies relevant to primate endometrial physiology. Here we report that P also increases KGF expression in the estrogen-primed mouse uterus. In addition, we found that P treatment of estrogen-primed mice induced an episode of apoptosis in the uterine luminal epithelium that lasted for 24 hours and then ceased, concomitant with the increase in KGF expression. Because KGF has cytoprotective effects in some tissues, we tested whether it could inhibit apoptosis in the uterus. In initial studies, spayed mice were primed for 2 days with estradiol (E) followed by 5 days of E+P. Tissues were sampled 1, 3 and 5 days after the E+P treatment started. KGF expression was negligible on day 1 but increased 10-12 fold on days 3 and 5 after P treatment began. Apoptotic index (number of apoptotic bodies/100 epithelial cells) was 39 q 2% after 1 day of E+P treatment and 0% after 3 and 5 days of E+P. To test for KGF effects, additional spayed mice were treated for 3 days (2 days of E, 1 day of E+P) and KGF (5 mg/kg in PBS) was given IP either for all 3 days or just on the third day, and all animals were sampled 24 hours later. Vehicle injected animals served as controls for the effects of KGF. Apoptotic indices were 44.5 q 2.02% in the vehicle controls, 5.8 q 2.13% after 3 days of KGF and 18 q 4.88% after 1 day of KGF. Both KGF treatments were significantly different from vehicle treatment at the p<.05 level (N=4 in each group). Histochemical detection of nuclear fragments by the TUNEL method confirmed these results. Measurements of KGF effects on various other apoptosis markers (e.g., p-53) are in progress. The data suggest that KGF may function not only as an epithelium-specific mitogen but also as a cytoprotective, anti-apoptotic agent. *All mice are treated in Bethesda and the tissues are shipped here. PART ll, SECTION A SCIENTIFIC SUBPROJECT FORM
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