Expression profiles of endometrial leukemia inhibitory factor, transforming growth factor beta 2 (TCF beta 2), and TGF beta 2 receptor in infertile bonnet monkeys

The expression profiles of leukemia inhibitory factor (LIF), transforming g rowth factor beta2 (TGF beta2), and transforming growth factor beta2 recept or (TGF beta 2R) were analyzed during the peri-implantation period in regul arly menstruating, fertile bonnet monkeys and in animals in which endometri al nonreceptivity was induced by administering an antiprogestin, onapriston e. Based on our previous experiences, a dose of 2.5 or 5 mg of onapristone was administered s.c. every third day during the menstrual cycle, because t hese dosages impair endometrial development without upsetting the normal go nadal endocrine profiles. Endometrial biopsy specimens were collected durin g the proliferative phase (estradiol levels about 200 pg/ml, n = 5) and per i-implantation period (Day 8 after midcycle peak in estradiol levels, n = 5 ) from normal ovulatory animals and during the peri-implantation period fro m onapristone-treated animals (n = 10). The biopsy specimens were processed to determine the expression patterns of LIF, TGF beta2, and TCFPZR by immu nohistochemical and reverse transcription-polymerase chain reaction (RT-PCR ) methods. Levels of both protein and mRNA for LIF, TCF beta2, and TGF beta 2R (analyzed by immunohistochemistry and RT-PCR, respectively) were greate r in the endometrial samples collected during the peri-implantation period compared to samples collected during the proliferative phase in control ani mals. Treatment with either of the two doses (2.5 or 5 mg) of onapristone c aused a significant (P < 0.05) down-regulation in the expression of LIF in the peri-implantation endometria. The endometrial expressions of TGF beta2 and TCF beta 2R mRNAs were reduced significantly in animals treated with 5 mg of onapristone, but not in those treated with the lower dose. However, i mmunoreactive TGF beta2 and TCF beta 2R proteins were significantly (P < 0. 05) down-regulated in the endometrial samples from both the 2.5- and 5-mg-t reated groups. The alterations observed in the expression patterns of LIF, TGF beta2, and TGF beta 2R were specific, because the expression levels of epidermal growth factor receptor remained unaffected in the endometria from the treated groups. The present study demonstrates derangement in the expr ession profiles of LIF, TGF beta2, and TCF beta 2R during the periimplantat ion period in infertile bonnet monkeys. It may be hypothesized that TCF bet a2 function is one of the early steps in the regulation of the progesterone -driven cascade of events leading to endometrial receptivity, and that any aberration in this step may adversely affect the subsequent molecular event s (i.e., expression of LIF). These data also suggest that potential aberrat ions in the functional network of locally produced cytokines and growth fac tors even may occur in an endometrium exposed to the optimal peripheral hor monal levels.