Chronic stimulation of the hypothalamus-pituitary-adrenal axis in rats by interleukin 1beta: central and peripheral mechanisms

Cytokine. 1996 Dec;8(12):910-9. doi: 10.1006/cyto.1996.0122.


The authors have studied mechanisms which could be involved in the sustained activation of the hypothalamus-pituitary-adrenal (HPA) axis during continuous infusion of rats with recombinant human interleukin-1beta (IL-1beta). First, the effects of 3 days of intracerebroventricular (i.c.v.) infusion of rats with IL-1 on plasma adrenocorticotropin (ACTH) and corticosterone (B) levels were investigated. Thereafter, changes in plasma ACTH and B levels were followed in rats intraperitoneally (i.p.) infused with IL-1beta after immunoneutralization of corticotropin-releasing hormone (CRH), hypophysectomy (HPX), macrophage depletion using dichloromethylene diphosphonate (Cl2MDP)-containing liposomes, adrenalectomy (ADX) and dexamethasone (DEX) administration, respectively. Infusion of IL-1beta i.c.v., even in doses as low as 0.1 microg/day, induced significant increases in plasma ACTH and B levels. HPX and ADX rats died within 18 h after starting the IL-1beta infusion (0.5 microg/day). Immunoneutralization of CRH significantly decreased and macrophage depletion significantly increased the stimulation of the HPA axis by IL-1 (4.0 microg/day). Administration of high doses of DEX completely abolished the stimulation of the HPA axis by IL-1beta (2.0 microg/day). The present study demonstrates that lower doses of IL-1beta were able to activate the HPA axis when infused i.c.v. compared with i.p. Regarding stimulation of the HPA axis by chronic i.p. infusion of IL-1beta the present study: (1) provides evidence that the CRH system is involved; (2) provides no evidence for a direct stimulatory effect of IL-1beta on the release of B by the adrenal gland which is of sufficient magnitude to resist the stress of chronic i.p. IL-1beta infusion; (3) shows that endogenous macrophage-derived mediators, induced by i.p. IL-1beta infusion, express an overall inhibitory rather than a stimulatory effect on the activity of the HPA axis; (4) demonstrates that exogenous administration of DEX blocks the effect of IL-1beta, which fits well in the concept of an immunoregulatory feedback between IL-1beta and glucocorticoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenalectomy
  • Adrenocorticotropic Hormone / blood
  • Animals
  • Antibodies / immunology
  • Corticosterone / blood
  • Corticotropin-Releasing Hormone / immunology
  • Dexamethasone / pharmacology
  • Humans
  • Hypophysectomy
  • Hypothalamo-Hypophyseal System / drug effects*
  • Injections, Intraperitoneal
  • Injections, Intraventricular
  • Interleukin-1 / pharmacology*
  • Macrophages / immunology
  • Pituitary-Adrenal System / drug effects*
  • Rats
  • Rats, Wistar
  • Recombinant Proteins / pharmacology
  • Sodium Chloride


  • Antibodies
  • Interleukin-1
  • Recombinant Proteins
  • Sodium Chloride
  • Dexamethasone
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Corticosterone