Elsevier

Neurobiology of Disease

Volume 39, Issue 3, September 2010, Pages 393-401
Neurobiology of Disease

Brain cyclooxygenase-2 mediates interleukin-1-induced cellular activation in preoptic and arcuate hypothalamus, but not sickness symptoms

https://doi.org/10.1016/j.nbd.2010.05.005Get rights and content

Abstract

Interleukin-1ß acts on the CNS to induce fever, neuroendocrine activation, and behavioral changes, but cannot passively cross the blood–brain barrier. According to a widely accepted hypothesis interleukin-1ß induces the synthesis of cyclooxygenase-2 at the blood–brain interface, which produces prostaglandins that diffuse into brain parenchyma to activate neurons. We studied the role of brain cyclooxygenase-2 in interleukin-1ß-induced fever, neuroendocrine and behavioral responses and cellular activation by intracerebroventricular infusion of the cyclooxygenase-2 inhibitor NS-398. Central cyclooxygenase-2 inhibition attenuated extracellular signal-regulated kinase-1/2 phosphorylation and c-Fos induction in the median preoptic area and arcuate hypothalamus, but not in other hypothalamic or brainstem structures, after intraperitoneal interleukin-1ß administration. However, the same treatment did not affect interleukin-1ß-induced fever, rises in corticosterone or anorexia. These findings moderate the prevailing view and indicate that brain cyclooxygenase-2-dependent prostaglandin production is important to activation of the median preoptic and arcuate hypothalamus, but not necessarily involved in fever, rises in plasma corticosterone and anorexia after peripheral interleukin-1ß administration.

Introduction

A large body of evidence indicates that immune cells produce the proinflammatory cytokine interleukin-1ß (IL-1ß) upon detection of bacterial lipopolysaccharide (LPS) fragments, which, in turn, acts on the nervous system to induce fever, neuroendocrine activation and reduce locomotor activity and food intake (Bluthe et al., 1992, Luheshi et al., 1996, Rivier et al., 1989). However, despite its profound effects on CNS functioning, IL-1ß cannot passively cross the blood–brain barrier (BBB) formed by brain endothelial cells.

According to a widely accepted hypothesis circulating IL-1ß induces synthesis of lipophilic prostaglandins at the BBB, which then diffuse into brain parenchyma to activate neuronal pathways controlling thermogenesis, neuroendocrine axes and behavior (Rivest, 1999). Anatomical studies have indeed shown that brain endothelial and perivascular macrophages express type 1 IL-1 receptors (Konsman et al., 2004) and that intravenous (iv) or intraperitoneal (ip) IL-1ß injection induces expression of the prostaglandin-producing enzymes cyclooxygenase-2 (COX-2) and prostaglandin E synthase (PGES) in these cells (Cao et al., 1996, Ek et al., 2001, Konsman et al., 2004, Lacroix & Rivest, 1998, Proescholdt et al., 2002, Schiltz & Sawchenko, 2002). However, endothelial-specific knockdown of IL-1 receptors abrogates iv, but not ip, IL-1ß-induced, fever, reduced locomotor activity and c-Fos expression in some hypothalamic nuclei (Ching et al., 2007). Although brain prostaglandin synthesis is generally assumed to mediate fever, blood-born albumin-bound prostaglandin E2 is sufficient to provoke fever (Romanovsky et al., 1999). Since iv IL-1 increases circulating prostaglandin E2 and favors its CNS entry (Davidson et al., 2001), mechanisms other than prostaglandin synthesis at the blood–brain interface may be important in cytokine-to-brain signaling after peripheral IL-1ß administration.

Interestingly, peripheral administration of COX-2-specific inhibitors and genetic COX-2-deficiency attenuate IL-1ß-induced fever, neuroendocrine activation or anorexia (Li et al., 2001, Parsadaniantz et al., 2000, Swiergiel & Dunn, 2002). However, these findings cannot be interpreted to indicate that peripheral COX-2-dependent prostaglandin production mediates fever and anorexia after IL-1ß administration, since COX-2 inhibitors readily enter the CNS (Ferrario & Bianchi, 2003, Okumura et al., 2006). It is, therefore, at present unclear whether peripheral or CNS COX-2 production is involved in cytokine-to-brain signaling after peripheral IL-1ß administration.

In the present study, we addressed the role of central nervous COX-2 in temperature, neuroendocrine and behavioral responses to ip IL-1ß injection. To do so, we studied the effects of intracerebroventricular (icv) administration of the selective COX-2 inhibitor NS-398 on ip IL-1ß-induced fever, increased plasma corticosterone and reduced food intake. Given that ip IL-1ß induces phosphorylation of Extracellular signal-Regulated Kinase-1/2 (ERK1/2) in rat brain (Nadjar et al., 2005) and that prostaglandin E2 phosphorylates ERK1/2 in vitro (Burkey & Regan, 1995, Desai & Ashby, 2001, Fujino et al., 2003), it can be used as a proximal marker of prostaglandin action. We, therefore, also studied the effects of central COX-2 inhibition on ip IL-1ß-induced ERK1/2 phosphorylation in the brain and compared it to c-Fos induction patterns.

Section snippets

Materials and methods

All surgical procedures and treatments were carried out in accordance with APA ethical standards for humane animal treatment and French legislation on animal experimentation. All reagents were obtained from Sigma-Aldrich (St. Louis, MI, USA) unless stated otherwise.

icv NS-398 attenuates spinal cord COX-2 dependent formalin-induced paw flinching

A one-way ANOVA on intraplantar formalin-induced behavioral changes showed that icv infusion of 2 µl of 25 µg/µl of NS-398, compared to its vehicle DMSO, reduced the spinal cord COX-2-dependent nociceptive hind paw flinching during the 20-min test period (F(1,8) = 5.72; p < 0.05; data not shown).

icv NS-398 did not alter ip IL-1ß-induced fever, anorexia, weight loss or rises in plasma corticosterone

A two-way repeated measures ANOVA on body temperature differences after ip and icv treatments revealed the expected significant effect of time (F(7,154) = 11.93; p < 0.0001) and a significant interaction between

Discussion

The main novel finding of the present study is that central COX-2 inhibition prevented ip IL-1ß-induced ERK1/2 phosphorylation and c-Fos expression in the median preoptic nucleus (MEPO) and arcuate hypothalamus (ARH), but not in other hypothalamic structures or the brainstem nucleus of the solitary tract (NTS). In addition, the same treatment did not alter ip IL-1ß-induced fever, anorexia, or rises in plasma corticosterone.

According to a widely accepted hypothesis circulating IL-1ß induces

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