PDE4 as a target in preterm labour
© Méhats et al; licensee BioMed Central Ltd. 2007
Published: 1 June 2007
Cyclic nucleotide phosphodiesterases (PDE) are the enzymes catalyzing the hydrolysis and inactivation of the second messengers, cAMP and cGMP. Eleven PDE families are described to date, and selective inhibitors of some PDEs families are currently used in clinic for treating cardiovascular disorders, erectile dysfunction, and pulmonary hypertension. Isoforms of the PDE4 family are involved in smooth muscle contraction and inflammation. PDE4 selective inhibitors are currently in clinical trials for the treatment of diseases related to inflammatory disorders. Because of their myorelaxant properties, we first examined their expression in human myometrium and uncover an increased expression of one specific isoform, PDE4B2, in the near-term myometrium as compared to myometrium in the nonpregnant state. Using human myometrial cells in culture, we demonstrated that PDE4B2 can be induced by its own substrate, under the control of one of the major utero-contractile agonists, PGE2, itself upregulated by the proinflammatory cytokine IL-1β. Functionally, augmentation of global PDE4 activity decreases the ability of β-adrenergic agonists (the most commonly used tocolytic drugs) to inhibit myometrial contraction at the end of pregnancy and during pathophysiological situations, such as persistent intrauterine inflammation which is a major cause of very preterm delivery. Currently exploring the anti-inflammatory properties of PDE4 inhibitors in gestational tissues, we recently demonstrated the ability of these drugs to block a persistent inflammatory response of the foetal membranes in Humans and to prevent inflammation-driven preterm delivery and foetal demise in mice. These data open up a new therapeutical strategy to prevent inflammation-induced preterm delivery and its sequelae in very preterm infants.
Tea leaf has been used for 2,000 years in traditional Chinese medicine for its therapeutical virtues before becoming a traditional drink. One of its main active ingredients, theophylline, is a selective inhibitor of cyclic nucleotide phosphodiesterases (PDE), which hydrolyses the second messengers, cAMP and cGMP. Eleven families of PDE are described to date with different substrate preference, kinetics and modulators . Selective PDE inhibitors of the type 3 and type 5 families are currently used in clinic, respectively for cardiac disease, erectile dysfunction, and pulmonary hypertension. PDE4 specifically hydrolyses cAMP with high affinity and PDE4 inhibitors are highly scrutinized because of their myorelaxant and anti-inflammatory properties.
We explored in parallel the molecular mechanism of the hormonal regulation of the PDE4 expression in primary culture of myometrial cells. Like in the tissue of origin, PDE4 is the major cAMP-hydrolyzing activity in these cells and the four PDE4 genes are expressed. An increase in intracellular cAMP concentration led to a significant increase in cAMP PDE activity through the selective induction of the short forms of the PDE4B and PDE4D genes, namely PDE4B2, PDE4D1 and PDE4D2 . Hence, PDE4 upregulation provides a feedback mechanism by which cells might adapt from sustained stimulation of the cAMP pathway. We then shown that prostaglandin E2, one of the major effectors of labour, can induce PDE4B2 and PDE4D short forms, through a cAMP-dependent pathway, in the myometrial smooth muscle cells . This regulation may occur during labour, when PGE2 concentration rises dramatically, but also in certain pathophysiological situations, with intrauterine inflammation, because we observed that the proinflammatory cytokine IL1β, by increasing PGE2concentration, is also able to induce PDE4B2 . Furthermore, impregnation of myometrial strips with PGE2 leads to a heterologous desensitization of the β-adrenergic system. This is translated by a decrease of the relaxant strength of β-adrenergic agonists and is reversed in the presence of PDE4 inhibitors . Therefore, a co-application of β-mimetics and PDE4 inhibitors may greatly improve the efficiency of the tocolysis in case of preterm labour.
Besides, because PDE4 activity is high in the amnion and the chorion, we established that not only the myometrium is a target for PDE4 inhibition but also the fetal membranes. These data are of importance because amniochorionic membranes are major sources of pro-inflammatory mediators and uterotonic agents. Indeed, treatment of amniochorionic explants with the membrane product of E. coli, the lipopolysaccharide (LPS), induced synthesis of a pro-and anti-inflammatory cytokine, TNFα and IL-10 respectively but also induced synthesis of prostaglandins (PGs) and metalloproteases (MMPs) . In addition, PDE4 activity was independently increased by LPS treatment. On this model of explants, we demonstrated that PDE4 selective inhibitors diminished greatly the production of TNFα whereas they enhanced the release of IL-10. They then decreased the production of PGE2 and MMP9. Recently, we derived primary cells from the different cell types present in amniochorionic membranes: amniotic epithelial cells, fibroblasts and chorionic epithelial cells, the choriotrophoblasts, which serve as models to identify signaling pathways involved in a local inflammation.
We wish to acknowledge the sponsorship of Ferring, PerkinElmer and Serono, who helped to cover publishing charges of the article. We are also indebted to the financial support and organization by the EU project SAFE (The Special Non-Invasive Advances in Fetal and Neonatal Evaluation Network, LSHB-CT-2004-503243) of the 2005 and 2006 PTL workshops, where data of this article were presented as oral communications.
This article has been published as part of BMC Pregnancy and Childbirth Volume 7, Supplement 1, 2007: Proceedings of the First and Second European Workshops on Preterm Labour of the Special Non-Invasive Advances in Fetal and Neonatal Evaluation (SAFE) Network of Excellence. The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2393/7?issue=S1.
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