Keratinocyte growth factor is up-regulated by estrogen in the porcine uterine endometrium and functions in trophectoderm cell proliferation and differentiation

Keratinocyte growth factor (KGF) is expressed by uterine endometrial epithe lial cells during the estrous cycle and during pregnancy in pigs, whereas K GF receptor is expressed in conceptus trophectoderm and endometrial epithel ia. In particular, KGF expression in the endometrium is highest on day 12 o f pregnancy. This corresponds to the period of maternal recognition of preg nancy in pigs, which is signaled by large amounts of estrogen secreted by c onceptus trophectoderm acting on the endometrium. Our hypothesis is that es trogens of conceptus origin stimulate endometrial epithelial KGF expression , and, in turn, secreted KGF stimulates proliferation and differentiation o f conceptus trophectoderm. To determine the factors affecting KGF expressio n in the uterus, endometrial explants from gilts on day 9 of the estrous cy cle were cultured in the presence of 17 beta -estradiol, catechol estrogens , or progesterone. 17 beta -Estradiol stimulated the expression of KGF (P < 0.05), whereas catechol estrogens had no effect (P > 0.05). Between days 9 and 15 of pregnancy, proliferating cell nuclear antigen was abundant in co nceptuses, but was barely detectable in uterine endometrial epithelia. To d etermine the effects of KGF on conceptus trophectoderm, porcine trophectode rm (pTr) cells were treated with recombinant rat KGF (rKGF). rKGF increased the proliferation of pTr cells (P < 0.01) as measured by [H-3]thymidine in corporation. rKGF elicited phosphorylation of KGF receptor and activated th e mitogen-activated protein kinase (ERK1/2) cascade in pTr cells. pTr cell differentiation was affected by rKGF, because it increased expression of ur okinase-type plasminogen activator, a marker for differentiation in pTr cel ls. Collectively, these results indicate that estrogen, the pregnancy recog nition signal from the conceptus in pigs, increases uterine epithelial KGF expression, and, in turn, KGF stimulates the proliferation and differentiat ion of conceptus trophectoderm.