Mjm. Vandermeer et al., CHRONIC STIMULATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS IN RATS BY INTERLEUKIN-1-BETA - CENTRAL AND PERIPHERAL MECHANISMS, Cytokine, 8(12), 1996, pp. 910-919
The authors have studied mechanisms which could be involved in the sus
tained activation of the hyp othalamus-pituitary-adrenal (HPA) axis du
ring continuous infusion of rats with recombinant human interleukin-1
beta (IL-1 beta). First, the effects of 3 days of intracerebroventricu
lar (i.c.v.) infusion of rats with IL-1 on plasma adrenocorticotropin
(ACTH) and corticosterone (B) levels were investigated, Thereafter, ch
anges in plasma ACTH and B levels were followed in rats intraperitonea
lly (i.p.) infused with IL-1 beta after immunoneutralization of cortic
otropin-releasing hormone (CRH), hypophysectomy (HPX), macrophage depl
etion using dichloromethylene diphosphonate (Cl(2)MDP)-containing lipo
somes, adrenalectomy (ADX) and dexamethasone (DEX) administration, res
pectively, Infusion of IL-1 beta i.c.v., even in doses as low as 0.1 m
u g/day, induced significant increases in plasma ACTH and B levels, HP
X and ADX rats died within 18 h after starting the IL-1 beta infusion
(0.5 mu g/day). Immunoneutralization of CRH significantly decreased an
d macrophage depletion significantly increased the stimulation of the
HPA axis by IL-1 (4.0 mu g/day). Administration of high doses of DEX c
ompletely abolished the stimulation of the HPA axis by IL-1 beta (2.0
beta g/day). The present study demonstrates that lower doses of IL-1 b
eta were able to activate the HPA axis when infused i.c.v. compared wi
th i.p. Regarding stimulation of the HPA axis by chronic i.p. infusion
of IL-1 beta the present study: (1) provides evidence that the CRH sy
stem is involved; (2) provides no evidence for a direct stimulatory ef
fect of IL-1 beta on the release of B by the adrenal gland which is of
suffcient magnitude to resist the stress of chronic i.p. IL-1 beta in
fusion; (3) shows that endogenous macrophage-derived mediators, induce
d by i.p. IL-1 beta infusion, express an overall inhibitory rather tha
n a stimulatory effect on the activity of the HPA axis; (4) demonstrat
es that exogenous administration of DEX blocks the effect of IL-1 beta
, which fits well in the concept of an immunoregulatory feedback betwe
en IL-1 beta and glucocorticoids.