Stimulation of endothelin B receptor modulates the inflammatory activationof rat astrocytes

Inside the brain tissue, endothelins play numerous important biological rol es. One of the targets, astrocytes, predominantly display endothelin recept or subtype B (ETB). On cultured primary rat astroglial cells, we analyzed t he effect of IRL1620, a selective ETB receptor agonist, on the production o f nitric oxide (NO) and the synthesis of interleukin (IL)-6 and tumor necro sis factor (TNF)-alpha. We performed these experiments in the presence or a bsence of interferon-gamma (lFN-gamma) and/or lipopolysaccharide(LPS). IRL1 620 decreases NO production under basal conditions and after IFN-gamma stim ulation. However,during LPS-induced NO production, IRL1620 enhances this re lease, The basal IL-6 secretion and especially the LPS-induced synthesis ar e enhanced by the IRL1620 stimulation. The LPS-dependent TNF-alpha producti on is increased by the ETB stimulation. The IRL1620-induced decrease of bas al NO production is not dependent on Ca2+ entry or on phospholipase C (PLC) activation, as:shown by the use of LaCl3 and U73122, respectively. In the presence of LPS, the IRL1620 potentiation of NO production is inhibited by LaCl3 and U73122. The IRL1620-induced increase of IL-6 is dependent on PLC activation. These results suggest that endothelins can have dual effects de pending on the costimulatory factors present. Endothelins thus have importa nt immunomodulatory functions in the brain.