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Department of Anesthesiology

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Prostaglandins mediate the ACTH response to interleukin-1-beta instilled into the hypothalamic median eminence.

TitleProstaglandins mediate the ACTH response to interleukin-1-beta instilled into the hypothalamic median eminence.
Publication TypeJournal Article
Year of Publication1994
AuthorsMcCoy JG, Matta SG, Sharp BM
JournalNeuroendocrinology
Volume60
Issue4
Pagination426-35
Date Published1994 Oct
ISSN0028-3835
KeywordsAdrenocorticotropic Hormone, Animals, Corticotropin-Releasing Hormone, Humans, Indomethacin, Interleukin-1, Male, Median Eminence, Prostaglandins, Radioimmunoassay, Rats, Recombinant Proteins, Stereotaxic Techniques, Stimulation, Chemical
Abstract

Interleukin-1 beta (IL-1 beta) is a potent ACTH secretagogue which activates the release of hypothalamic CRH. Direct injections of IL-1 beta into the hypothalamic median eminence (ME), a site which lacks a blood-brain barrier, has been shown to rapidly induce ACTH secretion. Therefore, the ME is a likely site whereby circulating IL-1 beta can access the brain to stimulate CRH and, consequently, ACTH secretion. To further evaluate this hypothesis, an angular stereotaxic approach was developed to localize the spread of IL-1 beta to the ME and to optimally separate the injectate from the hypothalamic paraventricular nucleus (PVN), another proposed site of IL-1 action. Studies of the diffusion of [125I]-IL beta (100 nl delivered over 60 s) showed that 97% remained within 200 microns of the ventral surface of the hypothalamus and 87% was contained within a radius of 550 microns of the injection site in the sagittal plane. Additional rats received recombinant human IL-1 beta (0.2-25.0 ng in 100 nl) into the ME (intra-ME). Plasma ACTH levels were significantly elevated by a much lower dose (0.5 ng, p < 0.001) of IL-1 beta than that previously reported. Responses appeared to be dose-dependent and ACTH was maximally stimulated by 2.0 ng IL-1 beta. Also, immunocytochemically labelled CRH in the ME was markedly depleted after intra-ME IL-1 beta. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, has been shown to block both the induction of CRH secretion by IL-1 beta from hypothalamic explants, as well as the ACTH response to intravenous IL-1 beta. Thus, indomethacin was used to determine whether PGs are mediators of the ACTH response to IL-1 beta delivered into the ME. The ACTH response was abolished (p < 0.005) when a low dose of indomethacin (1 mg/kg i.v.) was administered 20 min before intra-ME IL-1 beta (25 ng). Finally, plasma ACTH was elevated in a dose-dependent manner by the intra-ME administration of PGs. The hierarchy of ACTH responses to PGE2 were: CSF < 0.5 micrograms (p < 0.001) = 2.0 micrograms < 4.0 micrograms (p < 0.05). Responses to PGF2 alpha were: CSF < 0.5 micrograms (p < 0.001) < 2.0 micrograms (p < 0.05) = 4.0 micrograms. Since these PGs appear to activate different second-messenger systems, a submaximal dose of each was administered alone or in combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Alternate JournalNeuroendocrinology
PubMed ID7824084
Grant ListDA 04196 / DA / NIDA NIH HHS / United States
T-32-DA 07239 / DA / NIDA NIH HHS / United States