Elsevier

Placenta

Volume 28, Issues 5–6, May–June 2007, Pages 543-556
Placenta

The Role and Regulation of the Nuclear Factor Kappa B Signalling Pathway in Human Labour

https://doi.org/10.1016/j.placenta.2006.05.011Get rights and content

Abstract

Within the discipline of reproductive biology, our understanding of one of the most fundamental biological processes is lacking—the cellular and molecular mechanisms that govern birth. This lack of understanding limits our ability to reduce the incidence of labour complications. The incidence of labour complications including: preterm labour; cervical incompetence; and post-date pregnancies has not diminished in decades. The key to improving the management of human labour and delivery is an understanding of how the multiple processes that are requisite for a successful labour and delivery are coordinated to achieve a timely birth. Processes of human labour include the formation of: contraction associated proteins; inflammatory mediators (e.g. cytokines); uterotonic phospholipid metabolites (e.g. prostaglandins); and the induction of extracellular matrix (ECM) remodelling. Increasingly, it is becoming evident that labour onset and birth are the result of cross-talk between multiple components of an integrated network. This hypothesis is supported by recent data implicating various upstream regulatory pathways in the control of key labour-associated processes, including the activity of enzymes involved in the formation of prostaglandins and extracellular matrix remodelling, and mediators of inflammation. Clearly, the biochemical pathways involved in the formation of these mediators represent potential sites for intervention that may translate to therapeutic interventions to delay or prevent preterm labour and delivery. Available data strongly implicate the nuclear factor-κB (NF-κB) family as candidate upstream regulators of multiple labour-associated processes. Not only do these data warrant further detailed analysis of the involvement of these pathways in the process of human labour but also promise new insights into the key mechanisms that trigger birth and the identification of new therapeutic interventions that will improve the management of labour.

Section snippets

The process of human labour

A successful outcome to labour and delivery is dependent upon three processes: (i) fetal maturation consistent with extra-uterine survival; (ii) gestational and reproductive tract tissue remodelling (either by proteases that degrade ECM or by cell death, apoptosis); and (iii) the formation of contraction associated proteins and uterotonic agents that promote synchronous, appropriate myometrial contractions. Contemporary models of how normal, timely birth is achieved—of how these processes are

The nuclear factor κB signalling pathway

Regulation of gene expression is controlled by specific transcription factors. Inappropriate activation by transcription factors is thought to contribute to the aetiology of many pathophysiological disorders. There are four superclasses of transcriptional factors [7]. Members of superclass 1 contain basic domains, and include activator protein (AP)-1 and cyclic adenosine monophosphate (cAMP) response element (CRE) binding protein. Superclass 2 members contain zinc co-ordinating DNA binding

Identification of NF-κB proteins in human gestational tissues

Components of the NF-κB signalling pathway have been identified in a number of intrauterine cells and tissues. Using real-time quantitative polymerase chain reaction, King et al. [47] demonstrated the expression of mRNA transcripts encoding for NF-κB pathway intermediates, including IκB-α, IKK-γ, the protein kinases IKK-α and IKK-β and NIK, in first trimester decidua. NF-κB DNA binding activity has been detected in human cytotrophoblasts isolated from human term placentas [48]; primary amnion

Summary

It has become increasingly evident that labour onset and birth are the result of cross-talk between multiple components of an integrated network (Fig. 2). Over the last few years, it has been demonstrated that a common, central pathway involved in promoting the formation of pro-inflammatory mediators in human parturition is the nuclear transcription factor signalling pathway involving NF-κB. A role for the involvement of the NF-κB signalling pathway in both term and preterm human labour is

Acknowledgements

Dr Martha Lappas is in receipt of a Postdoctoral Research Fellowship from the Elizabeth and Vernon Puzey Foundation (2002–2005). Associate Professor Greg Rice is in receipt of a Principal Research Fellowship form the National Health and Medical Research Council of Australia.

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