Interleukin-1β Induces Phosphodiesterase 4B2 Expression in Human Myometrial Cells through a Prostaglandin E₂- and Cyclic Adenosine 3′,5′-Monophosphate-Dependent Pathway

Abstract

Intrauterine infections are important etiological factors of preterm labor. They trigger an increase in proinflammatory cytokines, in particular IL-1beta, that induces a cascade of events resulting in the production of potent effectors of myometrial contractility, such as the prostaglandin E(2) (PGE(2)). Within the smooth muscle cells, contractility is under the control of cAMP content, partly regulated by cAMP-phosphodiesterase 4 (PDE4), the predominant family of PDEs expressed in human myometrium. In the present study, using a model of inflammation of human myometrial cells in culture, we demonstrated that exposing the cells to IL-1beta resulted in a significant up-regulation of PDE4 activity through an increase in PDE4B2 mRNA and protein levels. The IL-1beta-induced PDE4 activity occurs after an increase in PGE(2) production and subsequent cAMP augmentation. Pretreatment with indomethacin or NS 398 completely blocked this long-term effect of IL-1beta, revealing a PGE(2)-dependent pathway. Accordingly, our results demonstrated that the PDE4B2 variant can participate in the regulation of the inflammatory reaction that occurs at term or in preterm labor and leads to myometrial contractions. Knowing the myorelaxant effect of PDE4 inhibitors and the implication of the PDE4B2 in the inflammatory process, this isoform may be an appropriate target for discovering antiinflammatory drugs to manage infection-induced preterm deliveries.

Vascular Smooth Muscle Cell Phenotype-Dependent Phosphodiesterase 4D Short Form Expression: Role of Differential Histone Acetylation on cAMP-Regulated Function

“…In this context, several reports have identified marked changes in PDE4 expression during changes in cellular phenotype. Thus, colleagues (Mehats et al, 1999, 2001;Oger et al, 2002) have reported that marked changes in PDE4 variant expression occurs at parturition and that this event correlates with reduced effectiveness of several pharmacological agents used to limit preterm labor. Likewise, Shepherd et al (2004) recently described a profound change in PDE4D isoform expression during differentiation of monocytes into macrophages that may account for differential effects of PDE4 inhibitors between these cell types.…”

Myometrial cytokines and their role in the onset of labour

“…IL-1β enhance myometrial contractility via different pathways, promoting basal and store-operated calcium entry (Tribe 2002), upregulating TrpC expression (calcium entry channels; Dalrymple et al 2004) and increasing the expression of selected phosphodiesterases, enzymes involved in the control of intracellular levels of cyclic nucleotides (Oger et al 2002). TNF-α reduces the expression of Galphas, the component of the G-protein receptor complex that links to adenylyl cyclase and which increases intracellular cAMP levels promoting myometrial relaxation (Chapman et al 2005).…”

Inflammatory pathways in female reproductive health and disease

“…For example, myocytes pre-incubated with IL1B display greater increases in intracellular calcium (which itself is linked to smooth muscle contraction) in response to stimuli compared with myocytes incubated in control media (Tribe et al 2003). IL1B also increases expression of COX2 (itself an initiator of myometrial contractions; Rauk & Chiao 2000) and phosphodiesterase activity in myocytes (Oger et al 2002) again stimulating contractions. Additionally, IL1B administration stimulates preterm labour in a mouse model (Romero & Tartakovsky 1992).…”