Adenosine-induced IL-6 expression in pituitary folliculostellate cells is mediated via A2b adenosine receptors coupled to PKC and p38 MAPK

1 Activation of adenosine receptors in folliculostellate (FS) cells of the pituitary gland leads to the secretion of IL-6 and vascular endothelial growth factor (VEGF). 2 We investigated the action of adenosine A2 receptor agonists on IL-6 and VEGF secretion in two murine FS cell lines (TtT/GF and Tpit/F1), and demonstrated a rank order of potency, 5'-N-ethylcarboxamidoadenosine (NECA) > 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido-adenosine > adenosine, suggesting mediation via the A2b receptor. 3 NECA-mediated IL-6 release was inhibited by the PLC inhibitor 1-[6-((17beta-3-methoxyestra-1,3,5(10)-tiene-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione, the PI3 kinase inhibitor wortmannin and the PKC inhibitors bisindolylmaleimide 1 and bisindolymaleimide X1 HCl (Ro-32-0432). 4 NECA-mediated IL-6 release was attenuated (< 50%) by the extracellular signal-regulated kinase MAPK inhibitor 2'-amino-3'-methoxyflavone, and completely (> 95%) inhibited by the p38 MAPK inhibitor 4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl)1H-imidazole. 5 NECA stimulates p38 MAPK phosphorylation that is inhibited by Ro-32-0432 but not by wortmannin. 6 Dexamethasone inhibits NECA-stimulated IL-6 and VEGF secretion. 7 These findings indicate that adenosine can stimulate IL-6 secretion in FS cells via the A2b receptor coupled principally to PLC/PKC and p38 MAPK; such an action may be important in the modulation of inflammatory response processes in the pituitary gland.