Pergamon Psychoneuroendocrinology, Vol. 19, No. 2, pp. 209-232, 1994 Copyright © 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0306-4530/94 $6.00 + .00 0306-4530(93)E0010-S REVIEW ACTIVATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS BY BACTERIAL ENDOTOXINS: ROUTES AND INTERMEDIATE SIGNALS FRED J.H. TILDERS, l ROEL H. DERIJK, 1. ANNE-MARIE VAN DAM, I VALERIE A.M. VINCENT, I KAREL SCHOTANUS, 1 and JEK H.A. PERSOONS 2 Departments of IPharmacology and 2Cell Biology, Research Institute Neurosciences Vrije Universiteit, Amsterdam, The Netherlands SUMMARY Peripheral administration of endotoxin induces brain-mediated responses, including activation of the hypothalamus-pituitary-adrenal (HPA) axis and changes in thermoregulation. This paper re- views the mechanisms by which endotoxin affects these responses. The effects on theroregulation are complex and include macrophage-dependent hyperthermic and hypothermic responses. Low doses of endotoxin, given IP, activate peripheral macrophages to produce interleukin (IL)-lfl, which enters the circulation and acts as a hormonal signal. IL-I 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-I, 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-E 2 (PGE2) and thereby activate the HPA axis in a macrophage-independent manner. INTRODUCTION THE STRESS CONCEPT of Hans Selye was primarily based on stimuli that disturbed the physical integrity of the individual. In his studies, administering toxins to animals, induc- ing tissue damage, or exposing animals to X-rays played an important role. Selye noted that this type of stimuli resulted in a general and stereotyped somatic response, known as the GeneralAdaptation Syndrome, which involves enlargement of the adrenals, involu- tion of the thymus, lymphopenia, and gastric ulcerations. These changes are associated with increased activity of the hypothalamus-pituitary-adrenal (HPA) axis and played a Address correspondence and reprint requests to: F.J.H. Tilders, Research Institute Neurosciences Vrije Universiteit, Faculty of Medicine, Department of Pharmacology, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. * Present address: NIMH, Dept. Intramural Res. Prog., Clin. Neuroendocrinology Branch, Bldg 10 Room 3S231, 9000 Rockville Pike, Bethesda, Maryland 20892, U.S.A. 209