The PDE4 inhibitor rolipram prevents NF-kappaB binding activity and proinflammatory cytokine release in human chorionic cells.
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.
Hervé
Roxane
R
Institut National de la Santé et de la Recherche Médicale, Unité 767, Paris, France.
Schmitz
Thomas
T
Evain-Brion
Danièle
D
Cabrol
Dominique
D
Leroy
Marie-Josèphe
MJ
Méhats
Céline
C
D002478:Cells, Cultured; D002823:Chorion / Q000187:drug effects* / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D058988:Phosphodiesterase 4 Inhibitors; D011485:Protein Binding; D021381:Protein Transport; D020889:Rolipram / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D008070:Lipopolysaccharides; D016328:NF-kappa B; D058988:Phosphodiesterase 4 Inhibitors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram