Prostaglandin E2 in immune-to-brain signaling

• Upon immune-challenge, signaling from the immune system to the brain triggers an array of central nervous responses that include fever, anorexia, hyperalgesia and activation of the hypothalamus-pituitary adrenal axis. These symptoms are dependent on cytokines produced at the site of inflammation. However, because cytokines cannot penetrate the blood-brain barrier, the mechanism by which cytokines activate the central nervous system has remained elusive. Among several hypotheses, it has been suggested that prostaglandin E2 (PGE2) synthesized at the blood-brain interface and subsequently binding to PGE2 receptors expressed on deep neural structures may be responsible for the immune-to-brain signaling.During inflammatory conditions PGE2 is produced from prostaglandin H2 by the inducible isomerase microsomal prostaglandin E synthase-1 (mPGES-1). By using in situ hybridization, we investigated the expression of this enzyme in the brain of rats subjected to immune challenge induced by intravenous injection of interleukin-1ß. We found that mPGES-1 mRNA had a very restricted and low expression in the brain of naive rats. However, in response to inunune challenge it was rapidly and heavily induced in cells of the cerebral vasculature. Further, we found that the cells expressing mPGES-1 co-expressed cyclooxygenase-2 mRNA and interleukin-1 receptor type 1 mRNA. Thus, circulating interleukin-1 may bind to brain vascular cells and induce the expression of cyclooxygenase-2 and mPGES-1, leading to the production of PGE2 that can diffuse into the brain and trigger central nervous responses. We also showed that the same mechanism may be operating in a model for autoimmune disease. Thus, rats with adjuvant-induced arthritis, a model of rheumatoid arthritis, displayed a similar mPGES-1 and cyclooxygenase-2 induction in interleukin-1 receptor bearing brain endothelial cells.To examine the functional role of the central induction of mPGES-1, we studied the febrile response in mice deficient in the gene encoding mPGES-1. These mice showed no fever and no central PGE2 production in response to immune challenge induced by intraperitoneal injection of the bacterial fragment lipopolysaccharide, demonstrating that PGE2 synthesized by mPGES-1 is critical for immune-induced fever.We also studied the expression of receptors for PGE2 in the parabrachial nucleus, an autonomic brain stem structure involved in the regulation of food intake, blood pressure and nociceptive processing. We found that neurons in the para brachial nucleus express PGE2 receptors of type EP3 and EP4 and that many of the EP3 and some of the EP4 expressing neurons in this nucleus are activated by immune challenge. The PGE2 receptor expressing neurons also expressed mRNAs for various neuropeptides, such as dynorphin, enkephalin, calcitonin gene related peptide and substance P. Taken together with previous observations, these findings indicate that the PGE2 receptor expressing cells in the parabrachial nucleus are involved in alterations in food intake and in nociceptive processing during immune challenge.In summary, these data show the presence of a mechanism, involving cerebrovascular induction of mPGES-1, that conveys an inflammatory message from the blood-stream through the blood-brain barrier to relevant deep neural structures. Further, the findings show that this mechanism is critical for the febrile response and is activated during both acute and prolonged inflammatory conditions. This identifies mPGES-1 as a potential drug target for the alleviation of central nervous symptoms of inflammatory disease, such as fever, pain and anorexia.

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