Related Experiment Video
Updated: Jul 3, 2026
Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells
Published on: January 18, 2017
The PDE4 inhibitor rolipram prevents NF-kappaB binding activity and proinflammatory cytokine release in human
Roxane Hervé1, Thomas Schmitz, Danièle Evain-Brion
1Institut National de la Santé et de la Recherche Médicale, Unité 767, Paris, France.
Abstract:
Spontaneous preterm delivery is linked to intrauterine inflammation. Fetal membranes are involved in the inflammatory process as an important source of mediators, and the chorion leave produces high levels of the proinflammatory cytokine TNF-alpha when stimulated by LPS. The transcription factor NF-kappaB is the main regulator of this inflammatory process and controls the production of cytokines by the chorion leave. Phosphodiesterase 4 inhibitors are recognized for their anti-inflammatory and myorelaxant effects. The purpose of this study was to investigate whether PDE4 inhibition affects the LPS signaling in human cultured chorionic cells. We showed that these cells express TLR4, the main LPS receptor, and exhibit a predominant PDE4 activity. Upon LPS challenge, PDE4 activity increases concomitantly to the induction of the specific isoform PDE4B2 and chorionic cells secrete TNF-alpha. LPS induces the nuclear translocation of the NF-kappaB p65 subunit and the activation of three different NF-kappaB complexes in chorionic cells. The presence of the PDE4 inhibitor rolipram reduces the TNF-alpha production and the activation of the three NF-kappaB complexes. These data indicate that the PDE4 family interacts with the LPS signaling pathway during the inflammatory response of chorionic cells. PDE4 selective inhibitors may thus represent a new therapeutic approach in the management of inflammation-induced preterm delivery.
Insights
Phosphodiesterase 4 (PDE4) inhibition reduces inflammation in fetal chorionic cells. This finding suggests PDE4 inhibitors could be a novel treatment for preventing preterm birth caused by intrauterine inflammation.
Area of Science:
- Reproductive Biology
- Immunology
- Pharmacology
Background:
- Spontaneous preterm delivery is associated with intrauterine inflammation.
- Fetal membranes, particularly the chorion leave, produce pro-inflammatory mediators like TNF-alpha in response to LPS.
- NF-kappaB is a key transcription factor regulating inflammatory cytokine production in chorionic cells.
Purpose of the Study:
- To investigate the effect of phosphodiesterase 4 (PDE4) inhibition on lipopolysaccharide (LPS) signaling in human cultured chorionic cells.
- To determine if PDE4 inhibition can modulate inflammatory responses in the context of preterm delivery.
Main Methods:
- Human chorionic cells were cultured and stimulated with LPS.
- Expression of Toll-like receptor 4 (TLR4) and PDE4 activity were assessed.
- TNF-alpha secretion, NF-kappaB p65 nuclear translocation, and NF-kappaB complex activation were measured.
- The effect of the PDE4 inhibitor rolipram was evaluated.
Main Results:
- Chorionic cells express TLR4 and exhibit significant PDE4 activity, with increased activity and PDE4B2 induction upon LPS challenge.
- LPS stimulation led to TNF-alpha secretion and NF-kappaB pathway activation, including nuclear translocation of p65.
- Rolipram treatment significantly reduced TNF-alpha production and NF-kappaB complex activation.
Conclusions:
- The PDE4 enzyme family is involved in the LPS signaling pathway within chorionic cells during inflammation.
- PDE4 inhibition effectively suppresses inflammatory responses in these cells.
- Selective PDE4 inhibitors show potential as a therapeutic strategy for managing inflammation-induced preterm delivery.
Related Concept Videos
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
01:28Nitric Oxide Signaling Pathway