Activation of the hypothalamus-pituitary-adrenal axis by bacterial endotoxins: Routes and intermediate signals

Activation of the hypothalamus-pituitary-adrenal axis by bacterial endotoxins: Routes and intermediate signals
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Fred J.H. TildersCorresponding Author Contact Information, 1, Roel H. DeRuk1, *, Anne-Marie Van Dam1, Valerie A.M. Vincent1, Karel Schotanus1 and Jek H.A. Persoons2

1Department of Pharmacology, Research Institute Neurosciences Vrije Universiteit, Amsterdam, The Netherlands

2Department of Cell Biology, Research Institute Neurosciences Vrije Universiteit, Amsterdam, The Netherlands

Available online 17 March 2003.

Abstract

Peripheral administration of endotoxin induces brain-mediated responses, including activation of the hypothalamus-pituitary-adrenal (HPA) axis and changes in thermoregulation. This paper reviews the mechanisms by which endotoxin affects these responses. The effects on theroregulaton are complex and include macrophage-dependent hyperthermic and hypothermic responses. Low doses of endotoxin, given IP, activate peripheral macrophages to produce interleukin (IL)-1β, which enters the circulation and acts as a hormonal signal. IL-1 may pass fenestrated endothelium in the median eminence to stimulate corticotropin-releasing hormone (CRH) secretion from the CRH nerve-terminals. In addition, IL-1 may activate brain endothelial cells to produce IL-1, IL-6, prostaglandins, etc., and secrete these substances into the brain. By paracrine actions, these substances may affect neurons (e.g., CRH neurons) or act on microglial cells, which show IL-1-induced IL-1 production and therefore amplify and prolong the intracerebral IL-1 signal. In contrast, high doses of endotoxin given IV may directly stimulate endothelial cells to produce IL-1. IL-6, and prostaglandin-E2 (PGE2) and thereby activate the HPA axis in a macrophage-independent manner.