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) alpha 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 TNF alpha, 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 TNF alpha to the development of apoptosis, the amount of TNF alpha 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 TNF alpha released by endometrial fragments obtained from various phases of the menstrual cycle was determined. The amount of TNF alpha released into the culture medium by the endometrium was low in the proliferative phase. However, the amount of released TNF alpha progressively increased in the secretory phase and peaked in the menstrual phase. TNFr-I, TNFr-II, Fas, BCL-2 and TNF alpha could be identified by Western blot analysis of proteins extracted from endometrium. Therefore, endometrial epithelium by virtue of expression of receptors of TNF alpha 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 TNF alpha.

Tumor Necrosis Factor-alpha as a possible auto-/paracrine factor affecting estrous cycle in the cat uterus

“…TNFR2 mRNA expression fluctuated during the human menstrual cycle and peaked in both stromal and epithelial cells at the late proliferative and the late secretory stage (Hunt et al 1996). However, results obtained by Tabibzadeh et al (1995) did not confirm this cycle-related pattern and demonstrated that TNFR2 was not affected by the menstrual cycle in humans, which is in accordance with the data collected here for the cat uterus. The overall findings suggest that TNFα exerts its auto-/paracrine function on uterine PG secretion under physiological conditions in cats mostly at diestrus and at estrus, but not at interestrus, which is in accordance with the highest mRNA expressions for TNFα and TNFR1.…”

The role of chorionic gonadotropin and Notch1 in implantation

“…Apoptosis was first described in the human endometrium in 1975 [56] and subsequently shown to be rare in the proliferative endometrium, whereas levels of apoptosis increase in secretory tissue and peaks during the menstrual phase [57,58]. Treatment with (h)CG or progesterone in the midsecretory phase inhibits apoptosis in late secretory phase, implying a role for embryonic signals in inhibiting apoptosis [59].…”

Apoptosis and apoptosis‐related factors Bcl‐2, Bax, tumor necrosis factor‐α, and NF‐κB in human endometrial hyperplasia and carcinoma

“…24 NF-B is present in the endometrium during the menstrual cycle, but its association with apoptosis in that tissue is unknown. 25 The expression patterns of the apoptosis-regulating genes for Bcl-2, Bax, and TNF-␣ are dependent on the menstrual cycle, 6,7,26 suggesting that these factors are at least partially regulated by ovarian steroids. The expression of TNF-␣ has been found to be highest in menstruating endometrium, 26 and the low Bcl-2/Bax ratio in late and menstruating endometrium increases the susceptibility of glandular cells to apoptosis.…”

“…25 The expression patterns of the apoptosis-regulating genes for Bcl-2, Bax, and TNF-␣ are dependent on the menstrual cycle, 6,7,26 suggesting that these factors are at least partially regulated by ovarian steroids. The expression of TNF-␣ has been found to be highest in menstruating endometrium, 26 and the low Bcl-2/Bax ratio in late and menstruating endometrium increases the susceptibility of glandular cells to apoptosis. 6,7 Previous investigators have described apoptosis in endometrial hyperplasia and carcinoma using morphologic recognition of apoptotic cells.…”