Interleukin 1 (IL-1) type I receptors mediate activation of rat hypothalamus-pituitary-adrenal axis and interleukin 6 production as shown by receptor type selective deletion mutants of IL-1beta.
The cytokine interleukin 1 (IL-1) plays an important role in the activation of the hypothalamus-pituary-adrenal (HPA)-axis and interleukin 6 (IL-6) production during infection or inflammation. Which of the interleukin-1 receptor types mediates these effects is not known. To investigate this issue a pharmacological approach was chosen by using recently developed IL-1 receptor type selective ligands. Rats were given one of various doses of recombinant human IL-1beta (rhIL-1beta; 1 and 10 microg/kg) and of several IL-1beta mutants (DeltaSND, DeltaQGE and DeltaI; 1, 10 and 100 microg/kg), that differ in their affinities for the IL-1 type I receptor but have similar affinities for the IL-1 type II receptor. One hour after intravenous administration of rhIL-1beta or IL-1beta mutants, plasma levels of ACTH, corticosterone (cort) and IL-6 were measured. Doses of 1 and 10 microg/kg rhIL-1beta markedly elevated plasma levels of ACTH, cort and IL-6. However, 10-100-fold higher doses of IL-1beta mutants DeltaSND and DeltaQGE and at least 100-fold higher doses of DeltaI have to be administered to increase plasma levels of ACTH, cort and IL-6. The potency differences correlate with their respective affinity for the type I receptor but not with that of the IL-1 type II receptor. It is concluded that IL-1beta induced ACTH, cort and IL-6 production is mediated by interleukin 1 type I receptors.
Van Dam
A M
AM
Research Institute Neurosciences Free University, Medical Faculty, Department of Pharmacology, Amsterdam, The Netherlands. amw.van_dam.pharm@med.vu.nl
Malinowsky
D
D
Lenczowski
M J
MJ
Bartfai
T
T
Tilders
F J
FJ
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D010913:Pituitary-Adrenal System / Q000502:physiology*; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D053573:Receptors, Interleukin-1 Type I; D053574:Receptors, Interleukin-1 Type II; D011994:Recombinant Proteins / Q000494:pharmacology
D007375:Interleukin-1; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D053574:Receptors, Interleukin-1 Type II; D011994:Recombinant Proteins; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone