IL-4 Amplifies the Pro-Inflammatory Effect of Adenosine in Human Mast Cells by Changing Expression Levels of Adenosine Receptors

Xiaoyang Hua,Warren C Naselsky,Stephen L Tilley,Janki Y Patel,Kelly D Chason

doi:10.1371/journal.pone.0024947

Abstract

Adenosine inhalation produces immediate bronchoconstriction in asthmatics but not in normal subjects. The bronchospastic effect of adenosine is largely mediated through adenosine-induced mast cell activation, the mechanism of which is poorly understood due to limitations in culturing human primary mast cells. Here, we show that human umbilical cord blood -derived mast cells incubated with the Th2 cytokine IL-4 develop increased sensitivity to adenosine. Potentiation of anti-IgE- induced and calcium ionophore/PMA-induced degranulation was augmented in mast cells cultured with IL-4, and this effect was reduced or abolished by pre-treatment with A2BsiRNA and selective A2B receptor antagonists, respectively. IL-4 incubation resulted in the increased expression of A2B and reduced expression of A2A adenosine receptors on human mast cells. These results suggest that Th2 cytokines in the asthmatic lung may alter adenosine receptor expression on airway mast cells to promote increased responsiveness to adenosine.

Highlights

Adenosine is an important modulator of inflammation that is believed to contribute to the pathogenesis of several chronic diseases, including asthma
In the BR-1 mast cell line derived from a canine mastocytoma, adenosine analogue NECA-induced degranulation is blocked by enprophylline, a selective A2B antagonist, suggesting that the A2B receptor mediates the pro-inflammatory effects of adenosine in this mast cell model [9]
When adenosine was added 15 s prior to, or 1 and 5 min after antigen challenge, no potentiation was observed. These findings indicate that adenosine added 15–30 min prior to antigen challenge can elicit a potentiating effect on anti-IgE-induced degranulation of human umbilical cord blood derived mast cells (HUCBMCs)

Summary

Introduction

Adenosine is an important modulator of inflammation that is believed to contribute to the pathogenesis of several chronic diseases, including asthma. Adenosine inhalation can elicit immediate bronchoconstriction [1].This effect on the airway can largely be eliminated by pretreatment with mast cell membrane stabilizers and H1 receptor antagonists, suggesting that the bronchoconstriction following adenosine challenge occurs indirectly through activation of mast cells [2,3]. Mast cells from most species express A2A, A2B and A3 adenosine receptors [4]. The receptor(s) mediating adenosineinduced mast cell activation has been controversial, which is partially due to high heterogeneity of mast cells. In the BR-1 mast cell line derived from a canine mastocytoma, adenosine analogue NECA-induced degranulation is blocked by enprophylline, a selective A2B antagonist, suggesting that the A2B receptor mediates the pro-inflammatory effects of adenosine in this mast cell model [9]. The BR-1 cell line has many features suggesting that it is intrinsically different from human mast cells

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