ACTIVATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS BY BACTERIAL-ENDOTOXINS - ROUTES AND INTERMEDIATE

Peripheral administration of endotoxin induces brain-mediated response s, including activation of the hypothalamus-pituitary-adrenal (HPA) ax is and changes in thermoregulation. This paper reviews the mechanisms by which endotoxin affects these responses. The effects on theroregula tion are complex and include macrophage-dependent hyperthermic and hyp othermic responses. Low doses of endotoxin, given IP, activate periphe ral macrophages to produce interleukin (IL)-1 beta, which enters the c irculation and acts as a hormonal signal. IL-1 may pass fenestrated en dothelium 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, prostagl andins, etc., and secrete these substances into the brain. By paracrin e actions, these substances may affect neurons (e.g., CRH neurons) or act on microglial cells, which show IL-1-induced IL-1 production and t herefore amplify and prolong the intracerebral IL-1 signal. In contras t, high doses of endotoxin given IV may directly stimulate endothelial cells to produce IL-1, IL-6, and prostaglandin-E(2) (PGE(2)) and ther eby activate the HPA axis in a macrophage-independent manner.