<p>Upon an inflammation the immune system signals the brain by secreted cytokines to elicit central nervous responses such as fever, loss of appetite and secretion of stress hormones. Since the blood brain barrier, (BBB) protects the brain from unwanted material, molecules like cytokines are not allowed to cross the barrier and enter the brain. However, it is clear that they in some way can signal the brain upon an inflammation. Many suggestions concerning this signaling has been made, one being that cytokines bind to receptors on the endothelial cells of the blood vessels of the brain and trigger the production of prostaglandins that can cross the BBB. This conversion is catalyzed by the enzyme cyclooxygenase-2, (COX-2), which is induced by transcription factors like NF-κB in response to cytokines. One of the central nervous responses to inflammatory stimuli is activation of the HPA-axis whose main purpose is glucocorticoid production. Glucocorticoids inhibit the inflammatory response by suppressing gene transcription of pro-inflammatory genes including those producing prostaglandins through direct interference with transcription factors such as NF-κB or initiation of transcription of anti-inflammatory genes like IκB or IL-10. It has however not been clear if glucocorticoids can target the endothelial cells of the brain in order to provide negative feed-back on the immune-to-brain signaling, and in that way inhibit central nervous inflammatory symptoms. An anatomical prerequisite for such a mechanism would be that the induced prostaglandin production occurs in cells expressing GR. This has however never been demonstrated. Here I show that a majority of the brain endothelial cells expressing the prostaglandin synthesizing enzyme COX-2 in response to immune challenge also express the glucocorticoid receptor, (GR). This indicates that immune-to-brain signaling is a target for negative regulation of inflammatory signaling executed by glucocorticoids and identifies brain endothelial GR as a possible future drug target for treatment of central nervous responses to inflammation such as fever and pain.</p>

Upon an inflammation the immune system signals the brain by secreted cytokines to elicit central nervous responses such as fever, loss of appetite and secretion of stress hormones. Since the blood brain barrier, (BBB) protects the brain from unwanted material, molecules like cytokines are not allowed to cross the barrier and enter the brain. However, it is clear that they in some way can signal the brain upon an inflammation. Many suggestions concerning this signaling has been made, one being that cytokines bind to receptors on the endothelial cells of the blood vessels of the brain and trigger the production of prostaglandins that can cross the BBB. This conversion is catalyzed by the enzyme cyclooxygenase-2, (COX-2), which is induced by transcription factors like NF-κB in response to cytokines. One of the central nervous responses to inflammatory stimuli is activation of the HPA-axis whose main purpose is glucocorticoid production. Glucocorticoids inhibit the inflammatory response by suppressing gene transcription of pro-inflammatory genes including those producing prostaglandins through direct interference with transcription factors such as NF-κB or initiation of transcription of anti-inflammatory genes like IκB or IL-10. It has however not been clear if glucocorticoids can target the endothelial cells of the brain in order to provide negative feed-back on the immune-to-brain signaling, and in that way inhibit central nervous inflammatory symptoms. An anatomical prerequisite for such a mechanism would be that the induced prostaglandin production occurs in cells expressing GR. This has however never been demonstrated. Here I show that a majority of the brain endothelial cells expressing the prostaglandin synthesizing enzyme COX-2 in response to immune challenge also express the glucocorticoid receptor, (GR). This indicates that immune-to-brain signaling is a target for negative regulation of inflammatory signaling executed by glucocorticoids and identifies brain endothelial GR as a possible future drug target for treatment of central nervous responses to inflammation such as fever and pain.