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  • Title: Theophylline inhibits the differentiation of human monocyte into dendritic cell potentially via adenosine receptor antagonism.
    Author: Yasui K, Kondo Y, Wada T, Yashiro M, Tsuge M, Morishima T.
    Journal: Clin Exp Allergy; 2009 Dec; 39(12):1857-65. PubMed ID: 20085598.
    Abstract:
    BACKGROUND: Theophylline has an anti-inflammatory action that may account for its clinical effectiveness in the reduction of inflammatory cells in the airways. Dendritic cells (DCs) are professional antigen-presenting cells, capable of priming naïve T cells, and play key roles in the activation of immune responses in asthma. OBJECTIVE: The purpose of this study was to investigate the effects of theophylline on human monocyte differentiation into DCs and whether this involved antagonism of adenosine receptors. METHODS: Peripheral human blood monocytes were cultured in the presence of granulocyte/macrophage-colony stimulating factor and IL-4 to induce DC differentiation. The cells were incubated with theophylline, KF17837 (a selective A2a receptor antagonist) and enprofylline (A2b receptor antagonist) and co-incubated with selective adenosine A1 and A2a receptor agonists, a phosphodiesterase inhibitor (rolipram) and adenosine deaminase (ADA) to determine their effects on DC differentiation. In addition, depletion of adenosine receptors by small interfering RNA (siRNA) was also examined. RESULTS: Monocytes differentiated into myeloid DCs in the culture system. The number of DCs was remarkably reduced by 60-70% when theophylline was administered at a therapeutic concentration. This effect was concentration-dependently exacerbated, was partly mediated by cellular apoptosis and was effectively reversed by the addition of the A1 agonists [2-chloro-N(6)-cyclopentyladenosin, N(6)-cyclohexyladenosine, and N-ethylcarboxamidoadenosine (NECA)] or the A2a agonist (CGS-21680, NECA). The depletion of the adenosine A1 receptor by siRNA and addition of ADA remarkably reduced DC differentiation. Meanwhile, both enprofylline and rolipram had little effect. CONCLUSION: Our findings suggest that the adenosine A1 (and possibly coordinated with A2a) receptors contribute to DC differentiation and survival. These findings provide further evidence that theophylline has an anti-inflammatory action in bronchial asthma.
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