The PDE4 Inhibitor Rolipram Prevents NF-κB Binding Activity and Proinflammatory Cytokine Release in Human Chorionic Cells

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-α when stimulated by LPS. The transcription factor NF-κB 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-α. LPS induces the nuclear translocation of the NF-κB p65 subunit and the activation of three different NF-κB complexes in chorionic cells. The presence of the PDE4 inhibitor rolipram reduces the TNF-α production and the activation of the three NF-κB 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.

Leptin-Mediated Increases in Catecholamine Signaling Reduce Adipose Tissue Inflammation via Activation of Macrophage HDAC4

“…Administration of LPS (30mg/kg) into adult C57BL/6J mice increased circulating concentrations of the pro-inflammatory cytokines (TNFα, IL12β) and promoted lethality within 1–2 days (Figures 1A,B and S1A). Co-administration of the phospho-diesterase 4 (PDE4) inhibitor Rolipram (5mg/kg) blocked effects of LPS on cytokine release and survival (Figures 1 and S1) (Herve et al, 2008). Moreover, exposure of cultured bone marrow macrophages (BMMs) to prostaglandin E2 (PGE2), a paracrine hormone that stimulates cAMP production (Okonogi et al, 1991), reduced pro-inflammatory cytokine mRNA amounts and secretion from cultured cells exposed to LPS (Figures 1C,D and S1B).…”

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

“…Studies in other systems have shown that PDE4 inhibitors can inhibit NF‐ κ B p65 activation and NF‐ κ B‐driven inflammatory mediator release (Herve et al. 2008; Kwak et al. 2005).…”

The Neuroimmune Transcriptome and Alcohol Dependence: Potential for Targeted Therapies

“…In addition, cAMP-specific PDE4 regulates LPS-TLR4 induced inflammatory cytokine expression in mouse models of liver fibrosis, a condition commonly attributed to alcohol abuse [70]. Finally, PDE4 inhibitors have been shown to reduce NF-κB binding, leading to decreased inflammatory cytokine production in macrophages [71]. A promis-future science group Review Warden, Erickson, Robinson, Harris & Mayfield ing preliminary study by Avila et al [72] showed that alcohol-induced activation of astrocytes and microglia in mouse brain was attenuated in PDE4b knockout mice and by pharmacological inhibition using a PDE4 inhibitor (rolipram, 5 mg/kg).…”