title: Activation of the hypothalamus-pituitary-adrenal axis by bacterial endotoxins: routes and intermediate signals.
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 thermoregulation are complex and include macrophage-dependent hyperthermic and hypothermic responses. Low doses of endotoxin, given IP, activate peripheral macrophages to produce interleukin (IL)-1 beta, 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 i.v. 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.
authors.affiliation: Department of Pharmacology, Research Institute Neurosciences Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: F J
authors.initials: FJ
authors.lastname: Tilders
authors.forename: R H
authors.initials: RH
authors.lastname: DeRijk
authors.forename: A M
authors.initials: AM
authors.lastname: Van Dam
authors.forename: V A
authors.initials: VA
authors.lastname: Vincent
authors.forename: K
authors.initials: K
authors.lastname: Schotanus
authors.forename: J H
authors.initials: JH
authors.lastname: Persoons
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000344:Afferent Pathways / Q000503:physiopathology; D000818:Animals; D003345:Corticosterone / Q000097:blood; D015232:Dinoprostone / Q000097:blood; D004730:Endothelium, Vascular / Q000276:immunology; D004731:Endotoxins / Q000276:immunology*; D005790:General Adaptation Syndrome / Q000276:immunology*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D007375:Interleukin-1 / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood*; D008262:Macrophage Activation / Q000276:immunology; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D000324:Adrenocorticotropic Hormone; D015232:Dinoprostone; D003345:Corticosterone