Effects of Peripheral Cytokine Injections on Multiple Unit Activity in the Anterior Hypothalamic Area of the Mouse

The brain and the immune system interact in a bidirectional manner. This study on neuroimmune circuitry investigated the hypothesis that circulating cytokines act as messengers in the communication from the immune system to the brain and that the anterior hypothalamus is an integral part of this pathway. It was predicted that, following tail vein injections in mice, the cytokines interleukin-1β (IL-1β), interleukin-2 (IL-2), and interleukin-6 (IL-6) would alter electrical activity in the anterior hypothalamus. Differential electrodes were used to record multiple unit activity, at 5-min intervals, immediately before and for 60 min following injections. IL-1β and IL-2 decreased activity in the lateral margin of the anterior hypothalamus. IL-2-responsive neurons seemed to be localized to this area, while IL-1β-sensitive neurons showed a larger area of distribution. A significant response following IL-6 administration was not demonstrated. The observed changes in electrical activity support the concept of the hypothalamus as a sensory integration site for the immune system. Alternative models for the mechanism of cytokine signaling are discussed.     

Cytokine-induced change in hypothalamic norepinephrine turnover: involvement of corticotropin-releasing hormone and prostaglandins

Changes in norepinephrine (NE) turnover in restricted brain regions were examined in rats after administration of the major mediators of the acute phase response, interleukin-1β (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF). An increase in NE turnover was observed after intraperitoneal injection of IL-1 (1 μg/rat) in the whole hypothalamus and several specific hypothalamic nuclei, but not in the medulla oblongata and cerebral cortex. The stimulatory effect of IL-1 was mimicked by an intracerebroventricular injection of much lower doses of IL-1 (10–100 ng/rat). This IL-1-induced increase in hypothalamic NE turnover was blocked by the pretreatment with either indomethacin (cyclooxygenase inhibitor) or anti-corticotropin releasing hormone (CRH) antibody but not by naloxone. Intracerebroventricular injection of CRH increased NE turnover not only in the hypothalamus but also in the medulla oblongata and cerebral cortex. However, prostaglandin (PG) E₂ and PGF_2α did not show such effect. It was therefore suggested that IL-1 activates noradrenergic neurons projecting to the hypothalamus by its direct action to the brain, and that CRH and eicosanoid-cyclooxygenase product(s) within the brain are involved in this process. In contrast, neither IL-6 nor TNF influenced brain NE turnover regardless of whether they were given intraperitoneally or intracerebroventricularly. Thus, although IL-6 and TNF, as well as IL-1, show common central effects such as fever and pituitary-adrenal activation, these effects may be independent of the activation of NE metabolism in the hypothalamus.     

Role of IL-1 beta and 5-HT2 receptors in midbrain periaqueductal gray (PAG) in potentiating defensive rage behavior in cat

Feline defensive rage, a form of aggressive behavior that occurs in response to a threat can be elicited by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Our laboratory has recently begun a systematic examination of the role of cytokines in the regulation of rage and aggressive behavior. It was shown that the cytokine, interleukin-2 (IL-2), differentially modulates defensive rage when microinjected into the medial hypothalamus and PAG by acting through separate neurotransmitter systems. The present study sought to determine whether a similar relationship exists with respect to interleukin 1-beta (IL-1 beta), whose receptor activation in the medial hypothalamus potentiates defensive rage. Thus, the present study identified the effects of administration of IL-1 beta into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of IL-1 beta into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus in a dose and time dependent manner. In addition, the facilitative effects of IL-1 beta were blocked by pre-treatment with anti-IL-1 beta receptor antibody, while IL-1 beta administration into the PAG had no effect upon predatory attack elicited from the lateral hypothalamus. The findings further demonstrated that IL-1 beta's effects were mediated through 5-HT(2) receptors since pretreatment with a 5-HT(2C) receptors antagonist blocked the facilitating effects of IL-1 beta. An extensive pattern of labeling of IL-1 beta and 5-HT(2C) receptors in the dorsal PAG supported these findings. The present study demonstrates that IL-beta in the dorsal PAG, similar to the medial hypothalamus, potentiates defensive rage behavior and is mediated through a 5-HT(2C) receptor mechanism.     

Central Nervous System IL-1β System and Neuropeptide Y mRNAs During IL-1β-induced Anorexia in Rats

Interleukin-1β (IL-1β) induces anorexia and neuropeptide Y (NPY) increases feeding by direct action in the central nervous system (CNS). IL-1β, depending on the dose, attenuates or blocks NPY-induced feeding. This suggests that IL-1β-NPY interactions may be involved in IL-1β-induced anorexia. Here, RNase protection assays were used to investigate the effects of the chronic intracerebroventricular (ICV) administration of IL-1β (at a dose that yields estimated pathophysiological concentrations in the cerebrospinal fluid) on mRNA levels of IL-1β system components and NPY in the cerebellum, parietofrontal cortex, hippocampus, hypothalamus, and midbrain. The results show that the chronic ICV administration of IL-1β (8.0 ng/24 h for 72 h) differentially induced IL-1β system components across brain regions in anorectic rats. IL-1β mRNA and IL-1 receptor antagonist (IL-1Ra) mRNA were induced similarly, exhibiting highest and lowest expression levels in the hypothalamus and hippocampus, respectively. IL-1 receptor type I (IL-1RI) mRNA and the soluble form of IL-1 receptor accessory protein (IL-1R AcP II) mRNA were also induced in the hypothalamus and cerebellum. NPY mRNA expression showed a small, but significant decrease in the hypothalamus. Heat-inactivated IL-1β (8.0 ng/24 h for 72 h) had no effect on the behavioral or molecular profiles. The results suggest that endogenous upregulation of IL-1β contributes to IL-1β-induced anorexia, and that modification of NPY mechanisms also may be involved.     

IL-1beta immunoreactive neurons in the human hypothalamus: reduced numbers in multiple sclerosis

Corticotropin-releasing hormone (CRH)-containing neurons in the paraventricular nucleus (PVN) in the hypothalamus of multiple sclerosis (MS) patients are hyperactivated. Since interleukin-1 (IL-1)beta is a powerful activator of CRH neurons, its immunohistochemical expression was studied in the postmortem hypothalamus of MS patients (n=11) and matched controls (n=11). Hypothalamic tissue of 10/11 MS patients showed demyelinating lesions that in many cases contained IL-1beta-immunoreactive (ir) macrophages and glial cells. In control subjects IL-1beta-ir was only sporadically found in glial cells. Interestingly, abundant IL-1beta-ir was also present in hypothalamic neurons. Neuronal IL-1beta co-localised with oxytocin and not with vasopressin or CRH. IL-1beta clearly yielded a less intense staining in neurons and numbers of IL-1-ir neurons in the PVN were 4.5-fold reduced in MS. We suggest that IL-1beta produced by activated glial cells in the hypothalamus of MS patients may contribute to the activation of the hypothalamic CRH neurons, while reduced expression of neuronal IL-1beta in MS patients may have consequences for neuroendocrine, behavioural or autonomic functioning.     

Potentiating role of interleukin 2 (IL-2) receptors in the midbrain periaqueductal gray (PAG) upon defensive rage behavior in the cat: role of neurokinin NK(1) receptors

Feline defensive rage is a form of aggression occurring in nature in response to a threatening condition and is elicited under laboratory conditions by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Since it has recently been shown that cytokines can modulate neurotransmitter release, the present study was designed to determine the effects of administration of interleukin 2 (IL-2) into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of relatively low doses of IL-2 into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus. The specificity of this phenomenon was supported by the following findings: (1) IL-2 induced effects were dose- and time-dependent, (2) the facilitative effects of IL-2 could be completely blocked by pre-treatment of the injection site with either anti-IL-2 or anti-IL-2 receptor antibody and (3) IL-2 administration into the PAG showed no effect upon another form of aggression, namely predatory attack, elicited from the lateral hypothalamus. The findings further demonstrated that the effects of IL-2 were mediated by an NK(1) receptor mechanism since pre-treatment of the PAG with an NK(1) receptor antagonist completely blocked the facilitating effects of IL-2. Immunocytochemical observations supported these findings by demonstrating an extensive pattern of labeling of IL-2Ralpha in the dorsal PAG. The present study thus demonstrates that IL-2 in the dorsal PAG potentiates defensive rage behavior and is mediated through an NK(1) receptor mechanism.     

Rat brain vascular distribution of interleukin-1 type-1 receptor immunoreactivity: relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli

Interleukin-1 beta (IL-1 beta) is thought to act on the brain to induce fever, neuroendocrine activation, and behavioral changes during disease through induction of prostaglandins at the blood-brain barrier (BBB). However, despite the fact that IL-1 beta induces the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) in brain vascular cells, no study has established the presence of IL-1 receptor type 1 (IL-1R1) protein in these cells. Furthermore, although COX inhibitors attenuate expression of the activation marker c-Fos in the preoptic and paraventricular hypothalamus after administration of IL-1 beta or bacterial lipopolysaccharide (LPS), they do not alter c-Fos induction in other structures known to express prostaglandin receptors. The present study thus sought to establish whether IL-1R1 protein is present and functional in the rat cerebral vasculature. In addition, the distribution of IL-1R1 protein was compared to IL-1 beta- and LPS-induced COX-2 expression. IL-1R1-immunoreactive perivascular cells were mostly found in choroid plexus and meninges. IL-1R1-immunoreactive vessels were seen throughout the brain, but concentrated in the preoptic area, subfornical organ, supraoptic hypothalamus, and to a lesser extent in the paraventricular hypothalamus, cortex, nucleus of the solitary tract, and ventrolateral medulla. Vascular IL-1R1-ir was associated with an endothelial cell marker, not found in arterioles, and corresponded to the induction patterns of phosphorylated c-Jun and inhibitory-factor kappa B mRNA upon IL-1 beta stimulation, and colocalized with peripheral IL-1 beta- or LPS-induced COX-2 expression. These observations indicate that functional IL-1R1s are expressed in endothelial cells of brain venules and suggest that vascular IL-1R1 distribution is an important factor determining BBB prostaglandin-dependent activation of brain structures during infection.     

Interleukin-6 receptor α is co-localised with melanin-concentrating hormone in human and mouse hypothalamus

Interleukin (IL)-6 deficient mice develop mature-onset obesity. Furthermore, i.c.v. administration of IL-6 increases energy expenditure, suggesting that IL-6 centrally regulates energy homeostasis. To investigate whether it would be possible for IL-6 to directly influence the energy homeostasis via hypothalamic regulation in humans and rodents, we mapped the distribution of the ligand binding IL-6 receptor α (IL-6Rα) in this brain region. In the human hypothalamus, IL-6Rα-immunoreactivity was detected in perikarya and first-order dendrites of neurones. The IL-6Rα-immunoreactive (-IR) neurones were observed posterior to the level of the interventricular foramen. There, IL-6Rα-IR neurones were located in the lateral hypothalamic, perifornical, dorsal and posterior hypothalamic areas, the hypothalamic dorsomedial nucleus and in the zona incerta. In the caudal part of the hypothalamus, the density of the IL-6Rα-IR neurones gradually increased. Double-labelling immunofluorescent studies demonstrated that IL-6Rα immunoreactivity was localised in the same neurones as the orexigenic neuropeptide, melanin-concentrating hormone (MCH). By contrast, IL-6Rα-immunoreactivity was not observed in the orexin B-IR neurones. To determine whether the observed expression of IL-6Rα is evolutionary conserved, we studied the co-localisation of IL-6Rα with MCH and orexin in the mouse hypothalamus, where IL-6Rα-immunoreactivity was present in numerous MCH-IR and orexin-IR neurones. Our data demonstrate that the MCH neurones of the human hypothalamus, as well as the MCH and orexin neurones of the mouse hypothalamus, contain IL-6Rα. This opens up the possibility that IL-6 influences the energy balance through the MCH neurones in humans, and both MCH and orexin neurones in mice.     

Gene expression changes in the hypothalamus provide evidence for regionally-selective changes in IL-1 and microglial markers after acute stress

Recent work from our laboratory and others has shown that certain stressors increase expression of the pro-inflammatory cytokine interleukin-1β (IL-1) in the hypothalamus. The first goal of the following studies was to assess the impact of acute stress on other key inflammatory factors, including both cytokines and cell surface markers for immune-derived cells resident to the CNS in adult male Sprague Dawley rats exposed to intermittent footshock (80 shocks, 90 s variable ITI, 5 s each). While scattered changes in IL-6 and GFAP were observed in the hippocampus and cortex, we found the hypothalamus to be exquisitely sensitive to the effects of footshock. At the level of the hypothalamus, mRNA for IL-1 and CD14 were significantly increased, while at the same time CD200R mRNA was significantly decreased. A subsequent experiment demonstrated that propranolol (20 mg/kg i.p.) blocked the increase in IL-1 and CD14 mRNA observed in the hypothalamus, while the decrease in CD200R was unaffected by propranolol. Interestingly, inhibition of glucocorticoid synthesis via injection of metyrapone (50 mg/kg s.c.) plus aminoglutethimide (100 mg/kg s.c.) increased basal IL-1 mRNA and augmented IL-1 and CD14 expression provoked by footshock. Injection of minocycline, a putative microglial inhibitor, blocked the IL-1 response to footshock, while CD14 and CD200R were unaffected. Together, these gene expression changes (i) provide compelling evidence that stress may provoke neuroinflammatory changes that extend well beyond isolated changes in a single cytokine; (ii) suggest opposing roles for classic stress-responsive factors (norepinephrine and corticosterone) in the modulation of stress-related neuroinflammation; (iii) indicate microglia within the hypothalamus may be key players in stress-related neuroinflammation; and (iv) provide a potential mechanism (increased CD14) by which acute stress primes reactivity to later immune challenge.     

Interleukin-1 beta depolarizes paraventricular nucleus parvocellular neurones

Interleukin-1 beta (IL-1 beta) is involved in hypothalamic regulation of corticotropin releasing hormone (CRH) secretion and consequent downstream modulation of the neuroimmune response. In this study, whole-cell patch clamp recordings of rat parvocellular neurones in a slice preparation of the paraventricular nucleus (PVN) of the hypothalamus were performed to examine the cellular effects of IL-1 beta. In response to 1 nm IL-1 beta, 65% of parvocellular neurones tested exhibited a clear depolarization, which was abolished in the presence of tetrodotoxin (TTX). This depolarization was partially dependent on nitric oxide formation, as demonstrated by attenuation of the response in the presence of N-omega-nitro-L-arginine methylester, a nitric oxide synthase inhibitor. The effects of IL-1 beta on responsive parvocellular neurones were associated with a decrease in the frequency of inhibitory post synaptic potentials (IPSPs). Bicuculline administration blocked the effects of IL-1 beta, suggesting that this cytokine modulates GABA-ergic output, resulting in a decrease in inhibitory input (IPSPs) and consequent depolarization. These data support the conclusion that IL-1 beta influences the excitability of parvocellular neurones in the PVN, as a secondary consequence of nitric oxide generation and modulation of GABAergic inhibitory input to these cells. They elucidate cellular correlates underlying the well-established neuroimmune roles of IL-1 beta in the paraventricular nucleus of the hypothalamus.     

Interleukin-1 (IL-1) stimulates the release of corticotropin-releasing factor (CRF) from superfused rat hypothalamo-neurohypophyseal complexes (HNC) independently of the histaminergic mechanism.

We demonstrated previously that interleukin-1 (IL-1) (recombinant human IL-1 alpha and -1 beta) stimulated the release of corticotropin-releasing factor (CRF) from the superfused rat hypothalamo-neurohypophyseal complex (HNC), independently of the cholinergic system. In the present study we studied the effects of IL-1 on the release of CRF not only from the HNC but also from the isolated hypothalamus of rats in a superfusion system to define the origin of measured CRF and the site of IL-1 action. We also studied the possible involvement of the histaminergic system in the mediation of the stimulation by IL-1. An increase in CRF was elicited from the HNC and the isolated hypothalamus in a dose-dependent manner by human recombinant IL-1 beta in concentrations of 0.1-10 nM with similar time courses. Histamine in concentrations of 1-100 nM also elicited qualitatively similar increases of CRF from these two types of explants. The increases in CRF release from the HNC induced by 10 nM of histamine were completely suppressed in the combined presence of pyrilamine (10 microM) and cimetidine (10 microM), an H1 and an H2 receptor antagonist, respectively. On the other hand, the increase in CRF release induced by 10 nM IL-1 beta was not affected by the combination of these two antagonists. These results indicate that IL-1 stimulates CRF release from the median eminence through an action on the hypothalamus, and that the stimulatory effect of IL-1 is probably independent of the histaminergic system.     

Interleukin-1β System (Ligand, Receptor Type I, Receptor Accessory Protein and Receptor Antagonist), TNF-α, TGF-β1 and Neuropeptide Y mRNAs in Specific Brain Regions During Bacterial LPS-Induced Anorexia

Bacterial lipopolysaccharide (LPS) or endotoxin induces neurological manifestations including anorexia. It is proposed that LPS-induced cytokine production is involved in the generation of neurological manifestations and in neuroinflammatory/immunological responses during Gram-negative infections. For example, LPS-induced effects can be blocked or ameliorated by the interleukin-1 receptor antagonist (IL-1Ra). Here, sensitive and specific RNase protection assays were used to investigate the effects of the intracerebroventricular (i.c.v.) administration of LPS on mRNA levels of interleukin-1β (IL-1β) system components, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, and neuropeptide Y (NPY) in the cerebellum, hippocampus, and hypothalamus. The same brain region sample was analyzed with all of the antisense probes. The data show simultaneous local induction of multiple cytokine components messenger ribonucleic acids (mRNAs) within specific brain regions in anorectic rats responding to i.c.v. administered LPS (500 ng/rat). Interleukin-1β and IL-1Ra had a similar mRNA induction profile (hypothalamus > cerebellum > hippocampus). Interleukin-1 receptor type I (IL-1RI) mRNA also increased in all three brain regions examined, and the soluble form of IL-1 receptor accessory protein (IL-1R AcP II) mRNA was induced in the hypothalamus. Tumor necrosis factor-α mRNA levels increased in the hypothalamus > hippocampus > cerebellum. Levels of membrane bound IL-1R AcP, TGF-β1, and NPY mRNAs did not change significantly in any brain region. The results suggest that: (1) endogenous up-regulation of IL-1β and TNF-α in the hypothalamus contribute to LPS-induced anorexia; and (2) the ratio IL-1Ra/IL-1β, and IL-1β ↔ TNF-α interactions may have implications for Gram-negative infections associated with high levels of LPS in the brain-cerebrospinal fluid.     

Effect of subdiaphragmatic vagotomy on bacterial DNA-induced IL-1beta expression in the mouse hypothalamus

We investigated whether bacterial DNA (CpG-DNA)-induced IL-1beta expression in the mouse hypothalamus is mediated via afferent vagus nerve. Subdiaphragmatic vagotomy did not modify the CpG-DNA (i.p.)-induced IL-1beta expression in the hypothalamus, indicating that CpG-DNA-induced IL-1beta expression is independent of the afferent vagus nerve originating from the subdiaphragmatic organs. On the other hand, we observed the Toll-like receptor 9 mRNA expression in the hypothalamus, suggesting that circulating CpG-DNA acts directly in the brain.     

Specificity of interleukin–1β-induced changes in monoamine concentrations in hypothalamic nuclei: blockade by interleukin-1 receptor antagonist

The purpose of this study was to examine specificity in the effects of interleukin-1β (IL-1β) on monoamines in various areas of the hypothalamus. Adult male rats were injected i.p. with saline or 2.5 or 5.0 μg of IL-1β or were pretreated with 500 μg of IL-1 receptor antagonist (IL-1ra) followed 5 min later by 5 μg of IL-1β. The paraventricular nucleus (PVN), arcuate nucleus (AN), median eminence (ME), and medial preoptic area (MPA) were microdissected and analyzed for neurotransmitter concentrations by high-performance liquid chromatography with electrochemical detection (HPLC-EC). In the PVN, IL treatment produced significant increases in the concentrations of norepinephrine (NE), dopamine (DA), DA metabolite dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), and its metabolite 5-hydroxyindoleacetic acid (5-HIAA). IL-1 treatment increased the concentrations of NE and DA in the AN but only of NE in the ME, and it was without any effect in the MPA. Pretreatment with IL-1ra completely blocked the IL-1 effects. It is concluded that IL-1 induces highly specific changes in monoamine metabolism in the hypothalamus, and the nature of these changes depends on specific hypothalamic nuclei.     

Timecourse and corticosterone sensitivity of the brain, pituitary, and serum interleukin-1beta protein response to acute stress

Activation of peripheral immune cells leads to increases of interleukin-1beta (IL-1beta) mRNA, immunoreactivity, and protein levels in brain and pituitary. Furthermore, IL-1beta in brain plays a role in mediating many of the behavioral, physiological, and endocrine adjustments induced by immune activation. A similarity between the consequences of immune activation and exposure to stressors has often been noted, but the potential relationship between stress and brain IL-1beta has received very little attention. A prior report indicated that exposure to inescapable tailshocks (IS) raised levels of brain IL-1beta protein 2 h after IS, but only in adrenalectomized (and basal corticosterone replaced) subjects. The studies reported here explore this issue in more detail. A more careful examination revealed that IL-1beta protein levels in hypothalamus were elevated by IS in intact subjects, although adrenalectomy, ADX (with basal corticosterone replacement) exaggerated this effect. IL-1beta protein increases were already present immediately after the stress session, both in the hypothalamus and in other brain regions in adrenalectomized subjects, and no longer present 24 h later. Furthermore, IS elevated levels of IL-1beta protein in the pituitary, and did so in both intact and adrenalectomized subjects. IS also produced increased blood levels of IL-1beta, but only in adrenalectomized subjects. Finally, the administration of corticosterone in an amount that led to blood levels in adrenalectomized subjects that match those produced by IS, inhibited the IS-induced rise in IL-1beta in hypothalamus and pituitary, but not in other brain regions or blood.     

IL-1beta induced changes in hypothalamic IL-1R1 and IL-1R2 mRNA expression in the rat

Interleukin-1 receptor (IL-1R1 and IL-1R2) mRNA expression was detected within the rat hypothalamus, a primary site of IL-1 action, using RT-PCR. Levels of expression were unchanged by cardiac saline-perfusion. However, intracerebroventricular (i.c.v.) administration of IL-1beta caused changes in receptor mRNA expression in non-perfused animals that were profoundly different to those observed in their saline-perfused counterparts. This study demonstrates the importance of perfusing tissue to remove blood cells when determining changes in IL-1 receptor mRNA expression.     

Serotonergic activation stimulates the pituitary-adrenal axis and alters interleukin-1 mRNA expression in rat brain

Interactions between neurotransmitters and immunomodulators within the central nervous system may be functionally relevant for communication between the immune system and the brain. Previous studies indicate that cytokines such as interleukin-1 (IL-1) alter activity of the serotonergic system at multiple levels. This study tested the hypothesis that serotonergic activation modulates cytokine mRNA expression in brain. Serotonergic activation was induced by injecting rats intraperitoneally (i.p.) prior to dark onset with the serotonin precursor L-5-hydroxytryptophan (5-HTP; 100 mg/kg). Cytokine mRNA expression in discrete brain regions at selected time points was determined by means of ribonuclease protection assay. Plasma corticosterone concentrations were also measured to determine if the hypothalamic-pituitary-adrenal axis is activated in response to this treatment, which potentially could exert feedback regulating cytokine message expression in brain. Plasma corticosterone was elevated for 4 h after 5-HTP administration. At this time IL-1alpha mRNA expression was reduced in the hippocampus, hypothalamus, and brainstem, and IL-1beta mRNA was reduced in the hippocampus. Six hours after 5-HTP injection, IL-1beta mRNA increased in the hypothalamus. These results show that activation of the serotonergic system affects cytokine message expression in rat brain, possibly by actions of corticosterone.     

Inhibition of leptin-induced IL-1beta expression by glucocorticoids in the brain

Leptin is an important circulating signal for the regulation of food intake and body weight. Glucocorticoids were suggested to play a physiological role in the feedback inhibition of immune/inflammatory responses. In the present study, we examined whether these neuroendocrine effects of glucocorticoids are linked to changes in the leptin-induced expression of IL-1beta and STAT3 activation in the brain. Intravenous injection of leptin induced IL-1beta expression in the hypothalamus. Pretreatment with dexamethasone dose dependently inhibited leptin-induced IL-1beta expression in the hypothalamus. Moreover, dexamethasone inhibited leptin-induced IL-1beta expression in the primary cultured glial cells. In contrast, pretreatment with dexamethasone did not inhibit leptin-induced STAT3 phosphorylation in the hypothalamus. These effects of dexamethasone may not be due to the change in the expression level of the leptin receptor Ob-Ra and Ob-Rb isoforms. Therefore, it is suggested that glucocorticoid negatively regulates leptin-induced IL-1beta expression in the brain.