Neuroendocrinology
Corticotropins and Neuroimmune Interactions
Prostaglandins Mediate the ACTH Response to lnterleukin-1-Beta Instilled into the Hypothalamic Median EminenceMcCoy J.G.a · Matta S.G.a,b · Sharp B.M.a,baEndocrine Neurosciences Laboratories, Minneapolis Medical Research Foundation, and bDepartments of Medicine, Hennepin County Medical Center and the University of Minnesota, Minneapolis, Minn., USA
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Article / Publication Details
Received: February 24, 1994
Accepted: June 08, 1994
Published online: April 09, 2008
Issue release date: 1994
Number of Print Pages: 10
Number of Figures: 0
Number of Tables: 0
ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)
For additional information: https://www.karger.com/NEN
Abstract
Interleukin-1β (IL-1β) is a potent ACTH secretagogue which activates the release of hypothalamic CRH. Direct injections of IL-1β 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-1β 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-1β 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-1β (100 nl delivered over 60 s) showed that 97% remained within 200 µm of the ventral surface of the hypothalamus and 87% was contained within a radius of 550 µm of the injection site in the sagittal plane. Additional rats received recombinant human IL-1β (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-1β than that previously reported. Responses appeared to be dose-dependent and ACTH was maximally stimulated by 2.0 ng IL-1β. Also, immunocytochemically labelled CRH in the ME was markedly depleted after intra-ME IL-1β. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, has been shown to block both the induction of CRH secretion by IL-lβ from hypothalamic explants, as well as the ACTH response to intravenous IL-1β. Thus, indomethacin was used to determine whether PGs are mediators of the ACTH response to IL-1β 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-1β (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 µg (p < 0.001) = 2.0 µg < 4.0 µg(p < 0.05). Responses to PGF2α were: CSF < 0.5 µg (p < 0.001) < 2.0 µg (p < 0.05) = 4.0 µg. Since these PGs appear to activate different second-messenger systems, a submaximal dose of each was administered alone or in combination. Additivity of the response, rather than synergy, was evident, since the overall ACTH level in response to the combination of PGE2 and PGF2α (0.5 µg each) was no greater than the sum of the two separate treatments. In summary, the ACTH response to IL-1β delivered into the ME appears to be mediated by local prostaglandins.
© 1994 S. Karger AG, Basel
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Article / Publication Details
Received: February 24, 1994
Accepted: June 08, 1994
Published online: April 09, 2008
Issue release date: 1994
Number of Print Pages: 10
Number of Figures: 0
Number of Tables: 0
ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)
For additional information: https://www.karger.com/NEN
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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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