Biological activity and brain actions of recombinant rat interleukin-1alpha and interleukin-1beta.
IL-1alpha and IL-1beta have potent effects on the central nervous system resulting in fever, activation of the hypothalamic-pituitary-adrenal axis and behavioural depression. These effects have mainly been studied in rats, using recombinant human and mouse IL-1. Because IL-1alpha and IL-1beta show some species specificity in the potency of their biological activities, the objective of the present work was to directly compare the effects of recombinant rat IL-1alpha and IL-1beta in the rat system as a first step to dissect out the mechanisms that are involved in these effects. In vitro, recombinant rat IL-1alpha and IL-1beta bound with the same affinity as human IL-1 to the rat insulinoma Rin m5F cell line that mainly expresses type I IL-1 receptors. This binding activated IL-1 receptors, as shown by induction of the synthesis of TNF-alpha mRNA. In vivo, recombinant rat IL-1alpha and IL-1beta enhanced body temperature, increased plasma levels of corticosterone and ACTH, and depressed social behaviour. All these effects were obtained at doses 100-1,000 fold lower when IL-1 was injected centrally than when it was administered peripherally, indicating that they are centrally mediated. The relative potencies of recombinant rat IL-1alpha and IL-1beta were not the same depending on the endpoint and the route of injection, indicating that different mechanisms are likely to be involved in the various effects of IL-1 on the brain.
Anforth
H R
HR
School of Biological Sciences, University of Manchester, UK.
Bluthe
R M
RM
Bristow
A
A
Hopkins
S
S
Lenczowski
M J
MJ
Luheshi
G
G
Lundkvist
J
J
Michaud
B
B
Mistry
Y
Y
Van Dam
A M
AM
Zhen
C
C
Dantzer
R
R
Poole
S
S
Rothwell
N J
NJ
Tilders
F J
FJ
Wollman
E E
EE
D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D003001:Cloning, Molecular; D004926:Escherichia coli; D005106:Exploratory Behavior / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D007276:Injections, Intraventricular; D007340:Insulinoma; D007375:Interleukin-1 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010190:Pancreatic Neoplasms; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000502:physiology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D012919:Social Behavior; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha