A2B adenosine receptors induce IL-19 from bronchial epithelial cells, resulting in TNF-alpha increase.

Adenosine is a signaling nucleoside that has been proposed to contribute to the pathogenesis of asthma and chronic obstructive pulmonary disease. Previous studies suggest that adenosine might play an important role in modulating levels of inflammatory mediators in the lung. Because airway epithelium is an important cellular source of inflammatory mediators, the objective of the present study was to determine whether adenosine affects the expression and release of inflammatory cytokines from human bronchial epithelial cells (HBECs). Among the four subtypes of adenosine receptors, the A(2B) receptor was expressed at the highest level. 5'-(N-ethylcarboxamido)-adenosine (NECA), a stable analog of adenosine, increased the release of IL-19 by 4.6- +/- 1.1-fold. A selective antagonist of the A(2B) receptor, CVT-6694, attenuated this effect of NECA. The amount of IL-19 released from HBEC was sufficient to activate a human monocytic cell line (THP-1) and increase the release of TNF-alpha. Furthermore, TNF-alpha was found to upregulate A(2B) receptor expression in HBECs by 3.1- +/- 0.3-fold. Hence, these data indicate that NECA increases the release of IL-19 from HBECs via activation of A(2B) receptors, and IL-19 in turn activates human monocytes to release TNF-alpha, which upregulates A(2B) receptor expression in HBECs. The results of this study suggest that there is a novel pathway whereby adenosine can initiate and amplify an inflammatory response which might be important in pathogenesis of inflammatory lung diseases.