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      Role of Several Mediators of Inflammation on the Mouse Hypothalamo-Pituitary-Adrenal Axis Response during Acute Endotoxemia

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          Cytokines secreted by bacterial endotoxin-activated immune cells are substances known to stimulate the hypothalamo-pituitary-adrenal (HPA) axis function. The present study was designed to better understand the effect of different mediators of inflammation, such as cytokines and histamine, on the acute HPA axis response induced by administration of a single dose of bacterial lipopolysaccharide (LPS) in adult, male, BALB/c mice. Two different experimental designs were set up. In the first design, mice (n = 8–11 per group) were injected i.p. with LPS (90 µg/kg body weight) and killed by decapitation 2 or 6 h after treatment. Additional groups of mice were pretreated i.p. 12 h before LPS treatment with: (a) 3–4 mg IgG/kg body weight of either an anti-tumor necrosis factor-α (TNF)-α, anti-interleukin (IL)-1β- or IL-6 serum; (b) IL-1 receptor antagonist (IL-1ra) (120 µg/kg body weight) immediately before LPS and also 3 h later (when animals were killed 6 h after LPS injection), or (c) 182 µg/kg body weight of clemastine, an antagonist of H<sub>1</sub> histaminergic receptors, 2 h before LPS treatment; animals were killed in a similar fashion to that described for treatment with LPS alone. In the second experimental design, mice were pretreated (i.p., 10 mg/kg body weight, 30 min before administration of a similar dose of LPS) with different blockers of histaminergic pathway function such as: (a) mepyramine, another anti-H<sub>1</sub>, (b) cimetidine, an H<sub>2</sub> receptor blocker, and (c) Rα-methylhistamine dihydrochloride, an H<sub>3</sub> presynaptic receptor agonist which inhibits histamine synthesis and output. These animals were then killed by decapitation 40 min after endotoxin treatment. After decapitation, trunk blood was collected for further determination of plasma levels of both ACTH and corticosterone (B) by specific assays. The results indicate that plasma levels of both ACTH and B were several-fold increased over baseline, 2 and 6 h after LPS administration. Two hours, the effect of LPS on ACTH output was not modified by pretreatment with anti-IL-1β IgG, anti-IL-6 IgG, anti-TNF-α IgG nor with IL-1ra, although IL-1ra treatment was able to fully block the IL-1β (35 µg/kg body weight)-stimulated HPA axis function, 1 and 2 h after cytokine administration. Six hours after LPS administration, anti-IL-1β and anti-TNF-α IgGs were both able to significantly reduce HPA axis response to the endotoxins, whereas anti-IL6 IgG had no effect. Anti-IL-1β IgG reduced only B secretion, whereas anti-TNF-α IgG decreased both ACTH and B secretion. The blockade of histaminergic pathway functions did not impede the LPS-induced ACTH and B release regardless of the product employed. The present results indicate that TNF-α, and to a lesser extent IL-1β, are the most relevant cytokines involved in HPA axis response to endotoxin administration. Our data also suggest that, in mice, HPA axis activation after infection appeared to be independent of stimualtion of the histaminergic pathway.

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          Most cited references 3

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          Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro.

          Clinical and experimental evidence suggests that shock, arthritis, osteoporosis, colitis, leukemia, diabetes, wasting and atherosclerosis are mediated, in part, by interleukin 1 (IL-1). Inhibition of this cytokine has been a strategy for studying disease and for new drug development. A naturally-occurring IL-1 inhibitor (IL-1 receptor antagonist, IL-1ra) that blocks binding of IL-1 to its receptors has been cloned and produced in recombinant organisms. IL-1ra reduces the severity of sepsis, colitis, arthritis and diabetes in animals and is presently being tested in humans with arthritis, shock and myelogenous leukemia.
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            A human myelomonocytic cell line, U937, produced an interleukin-1 (IL-1) receptor antagonist protein (IRAP) which was purified and partially sequenced. A complementary DNA coding for IRAP was cloned and sequenced. The mature translation product of the cDNA has been expressed in Escherichia coli and was an active competitive inhibitor of the binding of IL-1 to the T-cell/fibroblast form of the IL-1 receptor. Recombinant IRAP specifically inhibited IL-1 bioactivity on T cells and endothelial cells in vitro and was a potent inhibitor of IL-1 induced corticosterone production in vivo.
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              The role of interleukin-1 and tumor necrosis factor α in the neurochemical and neuroendocrine responses to endotoxin

               Adrian Dunn (1992)

                Author and article information

                S. Karger AG
                August 1999
                01 September 1999
                : 6
                : 5
                : 336-343
                aDivision of Endocrinology, Diabetology and Metabolism, University Hospital (CHUV), Lausanne, Switzerland, and bNeuroendocrine Unit, Multidisciplinary Institute on Cell Biology (IMBICE), La Plata, Argentina
                26393 Neuroimmunomodulation 1999;6:336–343
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 3, References: 37, Pages: 8
                Original Paper


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