The NF-kappaB pathway in human endometrium and first trimester decidua

Abstract

Nuclear factor kappa B (NF-kappaB) regulates proinflammatory genes and may be involved in inflammation associated with reproductive events e.g. menstruation, implantation. Activation of NF-kappaB involves several protein kinases and subsequent degradation of an endogenous inhibitor, IkappaBalpha. This study details expression of NF-kappaB pathway intermediates in human endometrium and first trimester decidua. Messenger RNA was detected for IkappaBalpha, and IkappaB kinase gamma (IKKgamma, a scaffolding protein) and the protein kinases, IKKalpha, IKKbeta, NF-kappaB inducing kinase (NIK), mitogen-activated protein kinase Erk kinase kinase 1 (MEKK1) and TANK-binding kinase 1 (TBK1) using real-time quantitative polymerase chain reaction (PCR). IkappaBalpha and TBK1 mRNA were increased in the perimenstrual phase of the menstrual cycle. This suggests that there is activation of NF-kappaB due to premenstrual progesterone withdrawal, since NF-kappaB activity increases IkappaBalpha gene expression. Differential expression of NF-kappaB pathway intermediates occurred when progesterone concentrations increased in early pregnancy; IKKalpha and NIK mRNA levels increased in decidua whilst IKKbeta and MEKK1 mRNA levels declined. Expression profiles of IKKalpha and NIK proteins were determined immunohistochemically. Both were detected in glandular epithelium and endothelium of endometrium. In decidua, both were present in epithelium and decidualized stromal cells. The results of this study suggest that NF-kappaB is activated during menstruation. During early pregnancy, NF-kappaB may also be activated (via IKKalpha-NIK) and may regulate the expression of molecules vital for implantation and successful pregnancy. However, pro-inflammatory signalling to NF-kappaB (via IKKbeta-MEKK1) may be down-regulated in early pregnancy, contributing to the immunosuppressive mechanisms which prevail at this time.