Activation of the hypothalamic-pituitary-adrenal axis in IL-1 beta-converting enzyme-deficient mice.
Interleukin-1beta (IL-1beta) plays a key role in immune, behavioral and neuroendocrine responses to inflammation or infection. IL-1beta could also be involved in the response of the hypothalamic-pituitary-adrenal (HPA) axis during stress. Mature IL-1beta derives from a 31-kD precursor (pro-IL-1beta) that is processed by IL-1beta-converting enzyme (ICE). Mice in which the ICE gene has been nullated by homologous recombination were used to investigate the role of IL-1beta in the HPA axis response. Plasma levels of corticosterone and adrenocorticotropic hormone (ACTH) in response to an intraperitoneal injection of 5 microg lipopolysaccharide (LPS) were similar in ICE-deficient mice and wild-type (WT) controls. In contrast, plasma ACTH response to restraint or to 200 ng of rat recombinant IL-1beta (rrIL-1beta) was higher in ICE-deficient mice as compared to WT animals. This hyperreactivity of the HPA axis in ICE knockout mice appears not to be related to the production of plasma IL-1beta or IL-6, which was similar to that of WT mice after rrIL-1beta injection. After lipopolysaccharide, ICE-deficient mice exhibited a smaller increase in plasma-immunoreactive IL-1beta and IL-6 as compared to WT controls. After restraint stress neither increase in plasma IL-1beta nor IL-6 was observed. The mechanisms responsible for the increased reactivity of the HPA axis in ICE-deficient mice may result from a higher sensitivity of the HPA axis to inflammatory cytokines or to cleavage products of pro-IL-1beta processed by non-ICE proteases.
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INSERM U.394 Neurobiologie Intégrative, Institut François-Magendie, Bordeaux, France.
Moze
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Kelley
K W
KW
Parnet
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Neveu
P J
PJ
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D020170:Caspase 1 / Q000235:genetics*; D003345:Corticosterone / Q000096:biosynthesis / Q000097:blood; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000008:administration & dosage / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000201:enzymology / Q000502:physiology*; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood; D012149:Restraint, Physical; D014158:Transcription, Genetic
D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D000324:Adrenocorticotropic Hormone; D020170:Caspase 1; D003345:Corticosterone