Endocrine Abstracts

Folliculostellate (FS) cells form a three-dimensional network within the anterior pituitary gland and play a key role in regulating the endocrine response to inflammation and anoxic stress. Adenosine, released under such conditions in high concentration, modulates a number of inflammatory processes and can regulate the activity of the hypothalamic-pituitary-adrenal (HPA) axis. The identities of the adenosine receptor (AR) subtypes mediating these responses, however, and the signal transduction pathways involved are not known. To address this we have analysed the distribution of ARs in folliculostellate cells (TtT/GF; Tpit/F1) and compared their effects on IL-6 expression following selective inhibition of the adenylate cyclase, phospholipase C and mitogen activated protein kinase (MAPK) cascades.
In TtT/GF cells, adenosine and adenosine receptor agonists (NECA, a universal AR agonist, and CGS 21680, a selective A2a receptor agonist) stimulated cAMP and IL-6 production with a potency order (NECA > CGS 21680 > adenosine) appropriate for mediation through the A2b adenosine receptor. NECA-mediated IL-6 release was partially inhibited by the phospholipase C inhibitor, U-73122 and the adenylate cyclase inhibitor, 2', 5'-dideoxyadenosine. It was also attenuated (< 50%) by the ERK (extracellular signal-regulated kinase) MAPK inhibitor, PD90859 and completely (>95%) inhibited by the p38 MAPK inhibitor SB203580. Additionally, NECA stimulated p38 MAPK phosphorylation but failed to have any effect on the phosphorylation of ERK 1/2 or JNK (c-Jun N-terminal kinase). The synthetic glucocorticoid dexamethasone also completely inhibited NECA-mediated IL-6 secretion. These findings suggest that the A2b receptor-induced stimulation of IL-6 secretion in FS cells is mediated via adenylate cyclase and phospholipase C coupled to p38 MAPK. Adenosine, by virtue of its role in regulating the HPA axis, is an important modulator of inflammatory response processes in the pituitary gland.