Signaling the brain in inflammation: The role of endothelial cells

Peripheral inflammation signals the brain primarily via blood-borne proinflammatory cytokines, released from activated immune cells. In addition to these cytokines, immune-brain signaling is known to involve another key mediator, prostaglandin E-2 (PGE(2)), the level of which is elevated in the brain during various inflammatory states and which acts to influence the central neuronal activity to evoke some, but not all, of the sickness behavior including fever and the activation of hypothalamopituitary-adrenal axis. Studies over the last decade have indicated that brain endothelial cells are the major source of PGE(2) under various inflammatory states. In this review, we highlight the significance of the endothelial mechanism in immune-brain signaling mediated by PGE(2), but discuss also the possible influence of other mechanisms on brain PGE(2) elevation.