SOMATOSTATIN INHIBITS INTERLEUKIN-6 RELEASE FROM RAT CORTICAL TYPE-I ASTROCYTES VIA THE INHIBITION OF ADENYLYL-CYCLASE

Interleukin 6 is a pleiotropic cytokine produced in the central nervou s system (CNS) that has been involved in both direct neurotrophic acti vities and in the regulation of the production of acute phase proteins both at peripheral and central levels. In rat cortical type I astrocy tes, interleukin 6 release is under the control of cAMP-protein kinase A and calcium-phospholipids-protein kinase C systems. Somatostatin is a neuropeptide, acting as a neurotransmitter, highly concentrated wit hin the CNS, where it has been involved in the modulation of learning and memory processes. The aim of this study was to characterize the ef fects of somatostatin on the release of interleukin 6 from rat cortica l type I astrocytes and the intracellular mechanisms involved in this activity. Our results show that somatostatin, in a concentration-depen dent manner, inhibited basal and forskolin-stimulated interleukin 6 re lease from rat cortical type I astrocytes in culture. The EC50 of the inhibitory action was calculated to be approximately 10 nM. Furthermor e, this effect of somatostatin was completely abolished by pretreating cortical astrocytes with pertussis toxin that, uncoupling, by ADP-ryb osylating, the inhibitory GTP-binding protein from the receptors, prev ents the activation of the intracellular effecters such as the adenyly l cyclase enzyme. To identify the intracellular mechanism mediating th e effects of somatostatin on the interleukin 6 release, we evaluated t he peptide modulation of basal and stimulated intracellular accumulati on of cAMP, In our experimental conditions somatostatin significantly inhibited both basal and forskolin-stimulated cAMP accumulation. Conve rsely, somatostatin did not affect the increase of interleukin 6 relea se induced by dibutyryl-cAMP, a nonhydrolizable cAMP analog that, bypa ssing the effects of somatostatin on adenylyl cyclase activity, direct ly activated protein kinase A, These observations support the hypothes is that somatostatin inhibitory activity on interleukin 6 release is m ediated by its effects on cAMP production. Somatostatin analog SMS 201 -995 did not affect interleukin 6 production either in basal or stimul ated conditions, Since, SMS 201-995 was reported to bind with high aff inity only to somatostatin receptors type 2, 3 and 5, the lack of effe ct of this compound on interleukin 6 release suggests that the inhibit ory action of somatostatin could be mediated by the activation of eith er type 1 or type 4 somatostatin receptors, In conclusion, our data de monstrate that the release of interleukin 6 from rat cortical type I a strocytes is inhibited by somatostatin through the activation of a som atostatin receptor coupled to the inhibition of adenylyl cyclase via a G-protein sensitive to pertussis toxin. (C) 1997 Academic Press.