Physiology: Site and menstrual cycle-dependent expression of proteins of the tumour necrosis factor (TNF) receptor family, and BCL-2 oncoprotein and phase-specific production of TNFα in human endometrium

Abstract

Apoptosis in human endometrial epithelium progressively increases from early to late secretory/menstrual phases and remains consistently more prominent in the basalis. It has been suggested that tumour necrosis factor (TNF) α secreted during the secretory/menstrual phases plays a role in induction of programmed cell death in these cells. In the present study, we characterized expression of receptors of TNFα, Fas antigen and BCL-2 in endometrial cells to gain insight as to whether this type of cell death in endometrium may be related to differential or preferential expression of these proteins at specific phases of the menstrual cycle. In addition, to relate production of TNFa to the development of apoptosis, the amount of TNFα released by human endometrium was measured. Immunostaining demonstrated that the TNF receptor (TNFr; p55/60)-I, TNFr-II (p75/80) as well as Fas protein were expressed in endometrial epithelium throughout the entire menstrual cycle. This expression was progressively diminished from the basalis towards the upper functionalis. In the proliferative phase, the expression of BCL-2 was prominent in the endometrial glands particularly in those residing in the basalis. This expression became weak as early as the third post-ovulatory day and remained low during the remaining phases of the menstrual cycle. The amount of TNFα released by endometrial fragments obtained from various phases of the menstrual cycle was determined. The amount of TNFα released into the culture medium by the endometrium was low in the proliferative phase. However, the amount of released TNFα progressively increased in the secretory phase and peaked in the menstrual phase. TNFr-I, TNFr-II, Fas, BCL-2 and TNFα could be identified by Western blot analysis of proteins extracted from endometrium. Therefore, endometrial epithelium by virtue of expression of receptors of TNFα as well as Fas protein is properly poised to respond to ligand signals that regulate apoptosis. Induction of apoptosis in endometrial epithelium and menstrual shedding may be related to loss of the protective effect of BCL-2 as well as to the amount of TNFα.