Endothelial activation is an intermediate step for peripheral lipopolysaccharide induced activation of paraventricular nucleus

doi:10.1016/S0361-9230(02)00951-6

Brain Research Bulletin

Volume 59, Issue 6, 15 February 2003, Pages 447-452

https://doi.org/10.1016/S0361-9230(02)00951-6 Get rights and content

Abstract

Peripheral injection of bacterial endotoxin lipopolysaccharide (LPS) activates the paraventricular nuclei of the hypothalamus (PVN), and consequently the hypothalamus-pituitary adrenal axis. Inflammatory cytokine interleukin-1 (IL-1) has been considered as a key mediator that translates the peripheral LPS stimulation into neuronal activation in the PVN. Several studies attempting to localize the expression of receptors for IL-1 (IL-1R), however, have failed to detect IL-1R on PVN neurons. It remains unclear, therefore, how IL-1 might stimulate the neurons of the PVN. In this study, we traced the cellular responsiveness to IL-1 by measuring the mRNA production of the cytokine responsive gene IκBα in the PVN. After either peripheral injection LPS or intracerebroventricular (i.c.v.) injection of IL-1β, IκBα mRNA was found mostly in endothelial cells of the brain with the highest level of expression in PVN blood vessels. In addition, both injections also induced the expression of cyclooxygenase-2 in brain endothelial cells. Pretreatment with indomethacin, a cyclooxygenase inhibitor, blocked LPS and IL-1 induced neuronal activation in the PVN, but did not reduce the induction of IκBα in PVN endothelium. These results show that IL-1 acting on the endothelial cells of the brain, particularly in the PVN, may be an intermediate step relating peripheral immune signals to the brain.

Section snippets

INTRODUCTION

Activation of PVN neurons by interleukin-1 (IL-1) was documented by the first set of studies that established a clear link between the immune system and the central nervous system. In these studies, peripherally administered IL-1 was found to stimulate the secretion of corticosterone by increasing the level of corticotropin releasing hormone (CRH) production from the PVN 1., 19.. Later, it was shown that activation of the immune system by bacterial endotoxin lipopolysaccharide (LPS) similarly

Animals

Male Sprague–Dawley rats (175–200 g, Harlan, IN) were group housed (three per cage) with food and water available ad lib. in a light (0600 to 1800 h) and temperature-controlled environment (20–22°C). All procedures were approved by the Ohio State University Animal Care and Use Committee.

Experimental Procedures

The animals were divided into eight experimental groups (n=4 in each group). For fresh frozen tissue collection, all animals were sacrificed by decapitation and their brains removed for analysis. Experiment 1

RESULTS

No c-fos and IκBα mRNA was detected in the PVN of saline injected animals (data not shown). The i.p. LPS injection induced both c-fos and IκBα expression in PVN (Fig. 1). The pattern of c-fos mRNA expression confined strictly to the border of the PVN (Fig. 1A), suggesting selective activation of c-fos in this nucleus. In contrast, although high levels of IκBα expression were detected in the PVN, low level, diffuse IκBα staining was also induced throughout the brain (Fig. 1B, arrowheads point to

DISCUSSION

Although PVN is considered a key brain region that mediates many of the neuroendocrine, behavioral, and physiological responses to peripheral immune challenge 15., 22., how this region is stimulated by peripheral immune signal initially generated outside of the blood–brain barrier is not fully understood. The results of the present study show that, when PVN neurons were activated by peripheral LPS, the induction of the cytokine responsive gene IκBα was restricted to the brain endothelium. The

Acknowledgements

This study was supported by a grant from the National Institutes of Health R01-NS40098 to Dr. Quan.

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Endothelial activation is an intermediate step for peripheral lipopolysaccharide induced activation of paraventricular nucleus

Abstract

Section snippets

INTRODUCTION

Animals

Experimental Procedures

RESULTS

DISCUSSION

Acknowledgements

J. Neuroimmunol.

Brain Res. Bull.

Brain Res.

Eur. J. Pharmacol.

J. Neuroimmunol.

Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1

Science

Indomethacin attenuates oxytocin and hypothalamic–pituitary–adrenal axis responses to systemic interleukin-1 beta

J. Neuroendocrinol.

Pyrogenic cytokines injected into the rat cerebral ventricle induce cyclooxygenase-2 in brain endothelial cells and also upregulate their receptors

Eur. J. Neurosci.

Evidence for an intramedullary prostaglandin-dependent mechanism in the activation of stress-related neuroendocrine circuitry by intravenous interleukin-1

J. Neurosci.

Type 1 interleukin-1 receptor in the rat brain: Distribution, regulation, and relationship to sites of IL-1-induced cellular activation

J. Comp. Neurol.

Effect of endotoxin in IL-1 beta-deficient mice

J. Immunol.

Visualization and characterization of interleukin 1 receptors in brain

J. Immunol.