Differential modulation of lipopolysaccharide-induced expression of inflammatory genes in equine monocytes through activation of adenosine A2A receptors

Adenosine is an endogenous nucleoside that has potent receptor-mediated immunomodulatory effects on macrophage/monocyte function. In this study, we determined the effects of an adenosine A2A receptor agonist, ATL313, on the expression of mRNAs for four pro-inflammatory mediators, IL-1β, IL-8, COX-2, and TNF-α, and the mRNA and protein for the anti-inflammatory cytokine, IL-10 in equine monocytes incubated with lipopolysaccharide (LPS). The results indicate that ATL313 significantly reduces LPS-induced expression of COX-2 and TNF-α, enhances the expression of IL-10 and IL-8, but does not alter the expression of IL-1β. These effects of ATL313 were reversed by co-incubation with the selective adenosine A2A antagonist ZM241385, and were mimicked by the cAMP analogue dibutyryl cAMP. These differential effects of adenosine A2A receptor activation were in contrast to those obtained using the P38 MAPK inhibitor, SB203580, which nearly abolished all LPS-induced changes in mRNA expression as well as the production of TNF-α protein. These findings, which indicate that adenosine A2A receptor activation modulates the transcription of several, but not all, pro-inflammatory mediators and exerts a synergistic effect on the induction of at least one anti-inflammatory cytokine, suggest that selective adenosine A2A agonists may reduce the early pro-inflammatory effects of endotoxemia in horses.