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      Inhibitory Effects of Endotoxin on LH Secretion in the Ovariectomized Monkey Are Prevented by Naloxone but Not by an Interleukin-1 Receptor Antagonist

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          Endotoxin (lipopolysaccharides, LPS), the pathogenic moiety of gram-negative bacteria, is a well-known trigger for the central release of cytokines. The objective of this study is to evaluate the effects of systemic endotoxin administration on LH and cortisol secretion in a non-human primate model and to investigate whether these endocrine effects are mediated by centrally released interleukin-1 (IL-1) using the receptor antagonist to IL-1 (IL-1ra). An additional objective is to investigate whether endogenous opioid peptides mediate these endocrine effects of LPS, using the opiate antagonist naloxone. The experiments were performed in long-term-ovariectomized rhesus monkeys. Blood samples for hormone determination were obtained at 15-min intervals for a period of 8 h, which included a 3-hour baseline period. Since the effective central dose of IL-1ra in the monkey was unknown, in the first experiment we tested the potency of several doses of this antagonist in preventing the effects of centrally administered IL-1α, a cytokine which is known to inhibit LH and stimulate cortisol release. Rhesus monkeys received a 30-min intracerebroventricular infusion of IL-1α (4.2 μg/30 min) alone or together with various doses of IL-1ra (30–180 μg/h i.c.v.). IL-1ra infusion was initiated 1 h before IL-1 and extended over the experimental period. As previously reported, IL-1α induced a significant inhibition of LH, to 36.5 ± 3.3% (mean ± SE) by 5 h as a percentage from the 3-hour baseline. This inhibitory effect was reversed by cotreatment with the 180 µg/h dose of IL-1ra (to 82.5 ± 3.8% by 5 h; NS vs. saline) but not with the lower doses. IL-1 stimulated cortisol release to 165.9 ± 7.7%, but this increase was prevented by IL-1ra (66.6 ± 8.9%; p < 0.05 vs. IL-1, NS vs. saline). In the second experiment, LPS (50 μg) was administered intravenously, alone or in combination with intracerebroventricular IL-1ra infusion. LPS induced a significant decrease in LH secretion (to 57.1 ± 5.2%). These effects were not reversed by intracerebroventricular administration of IL-1ra (52.5 ± 9.6%). Cortisol secretion increased in response to LPS, but this stimulatory effect was not affected by IL-1ra (178.3 ± 13.4 vs. 166.9 ± 5.7%). There were no effects of IL-1ra alone. In experiment 3, we investigated whether the opiate antagonist naloxone reverses the endocrine effects of endotoxin. Both LPS (50 μg) and naloxone (5-mg bolus + 5 mg/h) were infused intravenously. Naloxone was effective in preventing the inhibitory effect of LPS on LH (to 124.6 ± 22.1%, NS vs. saline) but not the increase in cortisol (to 166.7 ± 16.7%; p < 0.05 vs. saline, NS vs. LPS). Naloxone alone has no significant effect on LH or cortisol secretion. These data demonstrate that, in the ovariectomized monkey, a systemic inflammatory/immune- like stress challenge acutely inhibits tonic LH secretion while concomitantly stimulating cortisol release. Although endotoxin is known to affect central cytokine release, these endocrine effects do not require a mediatory role of central IL-1 in the primate. In contrast, endogenous opioid pathways appear to be involved in this process.

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          Most cited references 7

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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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            Regulation of the HPA axis by cytokines.

            Cytokines are a group of polypeptide mediators, classically associated with the regulation of immunity and inflammation. However, these peptides regulate not only local immune/inflammatory responses, but also elicit many CNS-mediated responses which accompany such immune/inflammatory reactions. This article reviews the evidence that interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNFalpha) produce hypothalamo-pituitary-adrenal (HPA) axis activation in response to various threats to homeostasis. To aid such an examination, and to gain insights into the potential mechanisms by which these cytokines influence the HPA axis, experimental findings are discussed within a framework of criteria. If a particular cytokine plays a significant role in the regulation of the HPA axis in response to a particular pathophysiology, then necessarily: (1) receptors for that cytokine should be present within tissues associated with the HPA axis; (2) administration of that cytokine should elicit HPA activation; (3) the HPA axis should be exposed to that cytokine; and (4) inhibition of the action of that cytokine should prevent HPA activation. The evidence discussed indicates that some, if not all, of these criteria are met for each of IL-1, IL-6, and TNFalpha. However, the extensive interactions between different cytokines, the broad spectrum of pathophysiologies associated with increased cytokine production (including inflammatory and non-inflammatory stresses), and the number of tissues/cells capable of either synthesizing or responding to cytokines, suggest that multiple mechanisms mediate the influence of cytokines on the HPA axis.
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              Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice


                Author and article information

                S. Karger AG
                December 1999
                15 December 1999
                : 7
                : 1
                : 6-15
                Departments of Obstetrics and Gynecology, and Physiology, and Center for Reproductive Sciences, College of Physicians and Surgeons, Columbia University, New York, N.Y., USA
                26415 Neuroimmunomodulation 2000;7:6–15
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 43, Pages: 10
                Original Paper


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