Studies of cytokine mediated regulation of central nervous functions : role of prostaglandins

Abstract: The communication between the immune system and the central nervous system (CNS) results in an array of centrally regulated illness responses, including fever and increased hypothalamus-pituitary-adrenal (HPA) axis activity. The mechanisms by which the immune system signals the brain across the blood-brain barrier have not been completely elucidated, but proinflammatory cytokines, like interleukin-1 (IL-1), are believed to act as important mediators. Alternative pathways by which circulating IL-1 may stimulate central neurocircuitries regulating illness responses and the potential contributory role of prostaglandins, particularly prostaglandin E2 (PGE2), are addressed in this thesis. One alternative hypothesis proposes that IL-1 may act indirectly upon the brain via activation of the vagus nerve. We demonstrated that intravenous (iv) injection of IL-1[beta] induces an increased discharge activity in gastric vagal afferents and expression of the cellular activation marker c-fos in the nodose ganglion of the vagus nerve. This IL-1-mediated activation is partially dependent on prostaglandins. Moreover, vagal afferents are likely to be acted on directly by both IL-1[beta] and PGE2, since the corresponding cellbodies in the nodose ganglion express mRNA encoding both the IL-1 receptor type I (IL-1Rt1) and the PGE2 receptor subtypes EP1, EP3 and EP4. Another proposed pathway includes 1L-1-mediated activation of vascular cells of brain blood vessels, resulting in synthesis and release of PGE2 into the brain parenchyma. Biosynthesis of PGE2 involves activities of the rate- limiting enzyme cyclooxygenase (COX) and the end-stage enzyme prostaglandin E synthase (PGES). We demonstrated that expression of mRNA encoding rat microsomal, glutathione dependent, PGES is strongly and selectively up-regulated by vascular cells of brain blood vessels following iv injection of IL-1[beta]. The same cells also express mRNA encoding the IL-1Rt1, as well as the inducible COX-2, indicating that circulating IL- 1[beta] specifically induces production of PGE2 via IL-1Rt1 dependent signalling within these cells. A proposed role for PGE2 as a mediator of IL-1-mediated regulation of central neurocircuitries controlling illness responses, requires the expression of PGE2 receptors on these neurocircuitries. We showed that mRNAs encoding the PGE2 receptor subtypes EP3 and EP4 are widely, but selectively, expressed throughout the rat brain, including within regions known to regulate fever, HPA axis activity, autonomic and nociceptive transmission. Moreover, EP3 receptor mRNA is expressed by IL-1-responsive cells in the nucleus of the solitary tract (NTS), ventrolateral medulla (VLM) and medial preoptic region, structures specifically believed to be involved in the control of HPA axis activity and fever.