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Rolipram Inhibits Phosphorylation and Activation of ERK/MAP Kinase Signalling Pathways in Allergen-activated Human Peripheral Mononuclear Cells

Author(s): Tz. Markova | M. Tabuchi | B. Alexieva | E. Nikolova | Y. Aragane | H. Higashino

Journal: International Journal of Pharmacology
ISSN 1811-7775

Volume: 6;
Issue: 5;
Start page: 600;
Date: 2010;
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Keywords: phosphodiesterase inhibitors | antigen presentation | Immune modulation | allergic disorders

Phosphodiesterase (PDE) enzymes catalyze breakdown of cAMP and cGMP, which is known to have potent immunomodulatory capacity. Here, we aimed at clarifying whether PDE4 is involved in allergen-induced activation of immunocompetent cells. To address this issue, human peripheral blood-derived mononuclear cells (PBMC) were cultured with mite antigen, dermatophagoides farinae (Der-f), in the presence or the absence of a specific PDE4 inhibitor, rolipram or a non-selective PDE inhibitor theophylline. Semiquantitative RT-PCR analysis demonstrated that stimulation of cells with Der-f led to upregulated expression of IL-5 mRNA, which was clearly downregulated by both inhibitors. Downregulation of Der-f-induced IL5 mRNA was similarly observed when cells were treated with U0126, a specific MEK/ERK inhibitor. This suggests that ERK signaling pathways are involved in this event. This was further supported by the observation that rolipram as well as theophyllin interfered with phospholylation of ERK1/2 induced by Der-f as determined by Western blot analysis using an antibody directed against phospholylated ERK1/2. Finally, immunostaining showed that stimulation to PBMC with Der-f led to nuclear translocation of AP-1 components (JunD, Fra-2), whose migration was inhibited by rolipram, indicating the interference with activation of AP-1 transcription factors. Together, the present study indicates that allergen-induced activation of immunocompetent cells was prevented by rolipram through interference with ERK1/2 signaling.
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