Human tumour necrosis factor: physiological and pathological roles in placenta and endometrium

Abstract

The cytokine tumour necrosis factor alpha (TNF) is a well known member of the TNF superfamily consisting of at least 18 ligands and 29 different receptors involved in numerous cellular processes. TNF signals through two distinct receptors TNFR1 and TNFR2 thereby controlling expression of cytokines, immune receptors, proteases, growth factors and cell cycle genes which in turn regulate inflammation, survival, apoptosis, cell migration, proliferation and differentiation. Since expression of TNF was discovered in amnion and placenta many studies demonstrated the presence of the cytokine and its receptors in the diverse human reproductive tissues. Whereas TNF has been implicated in ovulation, corpus luteum formation and luteolysis, this review focuses on the functions of TNF in human placental, endometrial and decidual cell types of normal tissues and also discusses its role in endometrial and gestational diseases. Physiological levels of the cytokine could be important for balancing cell fusion and apoptotic shedding of villous trophoblasts and to limit trophoblast invasion into maternal decidua. Regulation of the TNF/TNFR system by steroid hormones also suggests a role in uterine function including menstrual cycle-dependent destruction and regeneration of endometrial tissue. Aberrant levels of TNF, however, are associated with diverse reproductive diseases such as amniotic infections, recurrent spontaneous abortions, preeclampsia, preterm labour or endometriosis. Hence, concentrations, receptor distribution and length of stimulation determine whether TNF has beneficial or adverse effects on female reproduction and pregnancy.

Fig. 1

The diverse biological effects of TNF. Beneficial vs. adverse effects depend on local TNF concentrations, the expression pattern of TNF receptors and the abundance of inhibitors such as sTNFRs.

Fig. 2

TNF-dependent signalling pathways mediated through TNFR1 and TNFR2. Signalling of TNF through TNFR1 either results in formation of complex I and activation of NFκB (pathway 1) promoting inflammation, survival and differentiation or provokes cell death through complex II and activation of caspases (pathway 2). Recruitment of ASK-1 (pathway 3) induces JNK and AP-1 which in turn may initiate apoptosis or survival. TNFR2-dependent signalling may also promote cell death or survival through pathways 1 and 2, respectively, but also activate PI3K/AKT suppressing apoptosis and increasing promoting proliferation, migration and survival.

Fig. 3

An overview of the diverse functions of TNF in endometrium and placenta under physiological and pathological conditions.