Lipopolysaccharide and TNF-α modify adenosine A2A receptor expression and function in equine monocytes

Stimulation of adenosine A2A receptors results in anti-inflammatory effects in a variety of cell types. Lipopolysaccharide (LPS) and pro-inflammatory cytokines, such as TNF-α and IL-1, have been reported to up-regulate the expression of adenosine A2A receptors and thereby enhance the functional activity of adenosine A2A receptors in human and murine monocyte/macrophage cell lines and in monocytes/macrophages isolated from those species. In this study, we investigated the effects of LPS and TNF-α on the expression and functional activity of adenosine A2A receptors in isolated equine peripheral blood monocytes. The results of this study indicate that LPS and TNF-α up-regulate the transcription of adenosine A2A receptors for up to 24 h; the response to LPS was of greater magnitude than the response to TNF-α. In this study, incubation with LPS, but not with TNF-α, resulted in down-regulation of adenosine A3 receptor mRNA expression. Furthermore, incubation of these cells with LPS significantly increases the surface density of adenosine A2A receptors, and incubation with low concentrations of either LPS or TNF-α significantly increases the potency of the adenosine A2A receptor agonist, ATL313, to inhibit LPS-induced production of TNF-α. These findings suggest that the increased expression of adenosine A2A receptors and the enhanced functional potency of adenosine A2A receptor agonists after exposure to pro-inflammatory substances such as LPS or TNF-α may render adenosine A2A receptor agonists particularly important in the treatment of the systemic inflammatory response syndrome that occurs secondary to endotoxemia and bacterial infections in adult horses and neonatal foals.