atl-313 and Systemic-Inflammatory-Response-Syndrome

Stimulation of adenosine A(2A) receptors results in anti-inflammatory effects in a variety of cell types. Lipopolysaccharide (LPS) and pro-inflammatory cytokines, such as TNF-alpha and IL-1, have been reported to up-regulate the expression of adenosine A(2A) receptors and thereby enhance the functional activity of adenosine A(2A) 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-alpha on the expression and functional activity of adenosine A(2A) receptors in isolated equine peripheral blood monocytes. The results of this study indicate that LPS and TNF-alpha up-regulate the transcription of adenosine A(2A) receptors for up to 24h; the response to LPS was of greater magnitude than the response to TNF-alpha. In this study, incubation with LPS, but not with TNF-alpha, resulted in down-regulation of adenosine A(3) receptor mRNA expression. Furthermore, incubation of these cells with LPS significantly increases the surface density of adenosine A(2A) receptors, and incubation with low concentrations of either LPS or TNF-alpha significantly increases the potency of the adenosine A(2A) receptor agonist, ATL313, to inhibit LPS-induced production of TNF-alpha. These findings suggest that the increased expression of adenosine A(2A) receptors and the enhanced functional potency of adenosine A(2A) receptor agonists after exposure to pro-inflammatory substances such as LPS or TNF-alpha may render adenosine A(2A) 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.

Topics: Adenosine A2 Receptor Agonists; Animals; Animals, Newborn; Base Sequence; DNA Primers; Horse Diseases; Horses; Humans; In Vitro Techniques; Lipopolysaccharides; Mice; Monocytes; Piperidines; Radioligand Assay; Receptor, Adenosine A2A; Recombinant Proteins; RNA, Messenger; Systemic Inflammatory Response Syndrome; Triazines; Triazoles; Tumor Necrosis Factor-alpha