Human Tumour Necrosis Factor: Physiological and Pathological Roles in Placenta and Endometrium

Abstract 

The cytokine tumour necrosis factor α (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.

Keywords: Placenta, Trophoblast, Endometrium, TNF

Abbreviations: ASK-1, apoptosis-signalling kinase-1, AP-1, activator protein-1, bFGF, basic fibroblast growth factor, cIAP, cellular inhibitor of apoptosis protein, COX-2, cyclooxygenase-2, CRH, cortisol releasing hormone, ECM, extracellular matrix, EGF, epidermal growth factor, EMT, epithelial-mesenchymal transition, ERK, extracellular regulated kinases, Etk, endothelial/epithelial kinase, EVT, extravillous trophoblast, GnRH, gonadotropin-releasing hormone, HB-EGF, heparin-binding EGF-like growth factor, hCG, human chorion gonadotrophin, HLA, human leukocyte antigen, ICM, inner cell mass, IGF-1, insulin-like growth factor 1, IkB, inhibitor of kB, INFγ, interferon-γ, IUGR, intra-uterine growth restriction, JNK, c-Jun N-terminal kinase, LPS, lipopolysaccharide, MAP, mitogen activated protein, MCP-1, monocyte-chemotactic protein-1, MEKK, MAP kinase kinase kinase, MHC, major histocompatibility complex, MIF, migration inhibitory factor, MMP, matrix metallo proteinase, NFκB, nuclear factor kappa B, NK cells, natural killer cells, PAI-1, plasminogen activator inhibitor 1, PCOS, polycystic ovary syndrome, PDGF, platelet-derived growth factor, PG, prostaglandin, PI3K, phosphoinositid-3-kinase, RANTES, regulated upon activation normal T-cell expressed and secreted, RIP-1, serine/threonine kinase receptor interacting protein-1, SNP, single nucleotide polymorphism, SODD, silencer of death domain, STB, syncytiotrophoblast, sTNF, soluble tumour necrosis factor alpha, TACE, TNF-converting enzyme, TGF, transforming growth factor, Th1, T helper, Th1, T helper 2, TNF, tumour necrosis factor alpha, TNFR1, tumour necrosis factor receptor 1, TNFR2, tumour necrosis factor receptor 2, TRADD, TNFR-associated death domain, TRAF2, TNF receptor-associated factor 2, TRAIL, TNF-related apoptosis-inducing ligand, TUNEL, TdT-mediated dUTP-biotin nick end labelling, UAP, uterine activation protein, uPA, urokinase-type plasminogen activator, VCAM, vascular cell adhesion molecule, vCTB, villous cytotrophoblast, vEGF, vascular endothelial growth factor, vSMC, vascular smooth muscle cells, XAF1, XIAP associated factor 1, XIAP, X-linked inhibitor of apoptosis