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

Psychoneuroendocrinology. 1994;19(2):209-32. doi: 10.1016/0306-4530(94)90010-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Afferent Pathways / physiopathology
  • Animals
  • Corticosterone / blood
  • Dinoprostone / blood
  • Endothelium, Vascular / immunology
  • Endotoxins / immunology*
  • General Adaptation Syndrome / immunology*
  • Hypothalamo-Hypophyseal System / physiopathology*
  • Interleukin-1 / blood*
  • Interleukin-6 / blood*
  • Macrophage Activation / immunology
  • Pituitary-Adrenal System / physiopathology*
  • Signal Transduction / physiology


  • Endotoxins
  • Interleukin-1
  • Interleukin-6
  • Adrenocorticotropic Hormone
  • Dinoprostone
  • Corticosterone