Hypothalamic Interleukin-1 Research Articles

Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism.

Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation– and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle.

Key role for hypothalamic interleukin-6 in food-motivated behavior and body weight regulation

The pro-inflammatory role of interleukin-6 (IL-6) is well-characterized. Blockade of IL-6, by Tocilizumab, is used in patients with rheumatoid arthritis and those diagnosed with cytokine storm. However, brain-produced IL-6 has recently emerged as a critical mediator of gut/adipose communication with the brain. Central nervous system (CNS) IL-6 is engaged by peripheral and central signals regulating energy homeostasis. IL-6 is critical for mediating hypophagia and weight loss effects of a GLP-1 analog, exendin-4, a clinically utilized drug. However, neuroanatomical substrates and behavioral mechanisms of brain IL-6 energy balance control remain poorly understood. We propose that the lateral hypothalamus (LH) is an IL-6-harboring brain region, key to food intake and food reward control. Microinjections of IL-6 into the LH reduced chow and palatable food intake in male rats. In contrast, female rats responded with reduced motivated behavior for sucrose, measured by the progressive ratio operant conditioning test, a behavioral mechanism previously not linked to IL-6. To test whether IL-6, produced in the LH, is necessary for ingestive and motivated behaviors, and body weight homeostasis, virogenetic knockdown by infusion of AAV-siRNA-IL6 into the LH was utilized. Attenuation of LH IL-6 resulted in a potent increase in sucrose-motivated behavior, without any effect on ingestive behavior or body weight in female rats. In contrast, the treatment did not affect any parameters measured (chow intake, sucrose-motivated behavior, locomotion, and body weight) in chow-fed males. However, when challenged with a high-fat/high-sugar diet, the male LH IL-6 knockdown rats displayed rapid weight gain and hyperphagia. Together, our data suggest that LH-produced IL-6 is necessary and sufficient for ingestive behavior and weight homeostasis in male rats. In females, IL-6 in the LH plays a critical role in food-motivated, but not ingestive behavior control or weight regulation. Thus, collectively these data support the idea that brain-produced IL-6 engages the hypothalamus to control feeding behavior.

Effect of moxibustion on inflammatory cytokine levels in hippocampus and hypothalamus in rats with fatigue

To investigate the effect of moxibustion of "Zusanli "(ST36) on levels of inflammatory cytokines in the hippocampus and hypothalamus regions of rats with fatigue, so as to reveal its anti-fatigue mechanism. Twenty-four male Sprague-Dawley rats were randomly divided into normal control, fatigue model, and moxibustion groups, with 8 rats in each group. The fatigue model was established by chronic weight-loaded exhaustive swimming. During modeling, the rats in the moxibustion group were given moxibustion (3 moxa cones, about 8 min in duration) at bilateral ST36, once every other day for 11 times in total. The duration of exhausted swimming was observed, and ELISA was used to measure the contents of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon gamma (IFN-γ) in the hippocampus and hypothalamus tissues. The duration of exhausted swimming was obviously prolonged on day 14 and 21 after moxibustion intervention relevant to the model group (P<0.05, P<0.01). The contents of IL-1β， IL-6 and TNF-α in the hippocampus were significantly increased in the model group than in the normal group (P<0.01), and that of hippocampal IL-6 was considerably decreased in the moxibustion group than in the model group (P<0.05). The content of hippocampal IFN-γ was significantly lower in the model group than in the normal group (P<0.05) and was increased mildly after moxibustion (P>0.05). No significantly changes were found in the levels of hypothalamic IL-1β， IL-6, TNF-α and IFN-γ after modeling and moxibustion (P>0.05), and in the levels of hippocampal IL-1β， TNF-α and IFN-γ after moxibustion (P>0.05)．. Moxibustion can significantly down-regulate hippocampal IL-6 content in fatigue rats, which maybe contribute to its effect in alleviating fatigue. Further studies need being conducted to identify this conclusion.

Effects of chronic testosterone administration on the degree of preference for a high-fat diet and body weight in gonadal-intact and ovariectomized female rats

Energy balance and reproductive functions are closely linked in some species. The sex hormones (estrogens and androgens) are involved in the regulation of appetite, metabolism, body weight (BW), and body composition in mammals. Previously, we showed that the effects of testosterone on BW, appetite, and fat weight were markedly affected by alterations to the gonadal hormonal milieu. In this study, we examined whether testosterone administration changes food preferences and whether these effects of testosterone depend on gonadal status in female rats. We also evaluated the underlying mechanisms responsible for these effects, focusing on hypothalamic inflammation and endoplasmic reticulum (ER) stress. In gonadal-intact (sham) female rats, chronic testosterone administration promoted a preference for a high-fat diet (HFD) and increased BW gain, fat weight, and adipocyte size, whereas no such effects were observed in ovariectomized (OVX) rats. Testosterone administration increased hypothalamic interleukin-1 mRNA expression in the sham rats, but not the OVX rats. On the contrary, testosterone administration decreased the hypothalamic mRNA levels of ER stress-response genes in the OVX rats, but not the sham rats. These testosterone-induced alterations in OVX rats might represent a regulatory mechanism for preventing hypothalamic inflammation and the overconsumption of a HFD. In conclusion, testosterone’s effects on food preferences and the subsequent changes were affected by gonadal status. Testosterone-induced changes in hypothalamic inflammatory cytokine production and ER stress might be related to these findings.

Running Exercise in Obese Pregnancies Prevents IL-6 Trans-signaling in Male Offspring.

Maternal obesity is known to predispose the offspring to impaired glucose metabolism and obesity associated with low-grade inflammation and hypothalamic dysfunction. Because preventive approaches in this context are missing to date, we aimed to identify molecular mechanisms in the offspring that are affected by maternal exercise during pregnancy. Diet-induced obese mouse dams were divided into a sedentary obese (high-fat diet [HFD]) group and an obese intervention (HFD-running intervention [RUN]) group, which performed voluntary wheel running throughout gestation. Male offspring were compared with the offspring of a sedentary lean control group at postnatal day 21. HFD and HFD-RUN offspring showed increased body weight and white adipose tissue mass. Glucose tolerance testing showed mild impairment only in HFD offspring. Serum interleukin-6 (IL-6) levels, hypothalamic and white adipose tissue IL-6 gene expressions, and phosphorylation of signal transducer and activator of transcription 3 in HFD offspring were significantly increased, whereas HFD-RUN was protected against these changes. The altered hypothalamic global gene expression in HFD offspring showed partial normalization in HFD-RUN offspring, especially with respect to IL-6 action. Maternal exercise in obese pregnancies effectively reduces IL-6 trans-signaling and might be the underlying mechanism for the amelioration of glucose metabolism at postnatal day 21 independent of body composition.

Female-biased anorexia and anxiety in the Syrian hamster

Anorexia and anxiety cause significant mortality and disability with female biases and frequent comorbidity after puberty, but the scarcity of suitable animal models impedes understanding of their biological underpinnings. It is reported here that in adult or weanling Syrian hamsters, relative to social housing (SH), social separation (SS) induced anorexia characterized as hypophagia, weight loss, reduced adiposity, and hypermetabolism. Following anorexia, SS increased reluctance to feed, and thigmotaxis, in anxiogenic environments. Importantly, anorexia and anxiety were induced post-puberty with female biases. SS also reduced hypothalamic corticotrophin-releasing factor mRNA and serum corticosteroid levels assessed by RT-PCR and RIA, respectively. Consistent with the view that sex differences in adrenal suppression contributed to female biases in anorexia and anxiety by disinhibiting neuroimmune activity, SS elevated hypothalamic interleukin-6 and toll-like receptor 4 mRNA levels. Although corticosteroids were highest during SH, they were within the physiological range and associated with juvenile-like growth of white adipose, bone, and skeletal muscle. These results suggest that hamsters exhibit plasticity in bioenergetic and emotional phenotypes across puberty without an increase in stress responsiveness. Thus, social separation of hamsters provides a model of sex differences in anorexia and anxiety during adulthood and their pathogeneses during adolescence.

Metabolic syndrome induces inflammation and impairs gonadotropin-releasing hormone neurons in the preoptic area of the hypothalamus in rabbits

Rabbits with high fat diet (HFD)-induced metabolic syndrome (MetS) developed hypogonadotropic hypogonadism (HH) and showed a reduced gonadotropin-releasing hormone (GnRH) immunopositivity in the hypothalamus. This study investigated the relationship between MetS and hypothalamic alterations in HFD-rabbits. Gonadotropin levels decreased as a function of MetS severity, hypothalamic gene expression of glucose transporter 4 (GLUT4) and interleukin-6 (IL-6). HFD determined a low-grade inflammation in the hypothalamus, significantly inducing microglial activation, expression and immunopositivity of IL-6, as well as GLUT4 and reduced immunopositivity for KISS1 receptor, whose mRNA expression was negatively correlated to glucose intolerance. Correcting glucose metabolism with obetcholic acid improved hypothalamic alterations, reducing GLUT4 and IL-6 immunopositivity and significantly increasing GnRH mRNA, without, however, preventing HFD-related HH. No significant effects at the hypothalamic level were observed after systemic anti-inflammatory treatment (infliximab). Our results suggest that HFD-induced metabolic derangements negatively affect GnRH neuron function through an inflammatory injury at the hypothalamic level.

Sleep deprivation attenuates endotoxin-induced cytokine gene expression independent of day length and circulating cortisol in male Siberian hamsters (Phodopus sungorus)

Sleep is restorative, whereas reduced sleep leads to negative health outcomes, such as increased susceptibility to disease. Sleep deprivation tends to attenuate inflammatory responses triggered by infection or exposure to endotoxin, such as bacterial lipopolysaccharide (LPS). Previous studies have demonstrated that Siberian hamsters (Phodopus sungorus), photoperiodic rodents, attenuate LPS-induced fever, sickness behavior and upstream pro-inflammatory gene expression when adapted to short day lengths. Here, we tested whether manipulation of photoperiod alters the suppressive effects of sleep deprivation upon cytokine gene expression after LPS challenge. Male Siberian hamsters were adapted to long (16 h:8 h light:dark) or short (8 h:16 h light:dark) photoperiods for >10 weeks, and were deprived of sleep for 24 h using the multiple platform method or remained in their home cage. Hamsters received an intraperitoneal injection of LPS or saline (control) 18 h after starting the protocol, and were killed 6 h later. LPS increased liver and hypothalamic interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF) gene expression compared with vehicle. Among LPS-challenged hamsters, sleep deprivation reduced IL-1 mRNA levels in liver and hypothalamus, but not TNF. IL-1 attenuation was independent of circulating baseline cortisol, which did not increase after sleep deprivation. Conversely, photoperiod altered baseline cortisol, but not pro-inflammatory gene expression in sleep-deprived hamsters. These results suggest that neither photoperiod nor glucocorticoids influence the suppressive effect of sleep deprivation upon LPS-induced inflammation.

Influence of hypothalamic IL-6/gp130 receptor signaling on the HPA axis response to chronic stress.

Abnormal basal activity and stress-evoked reactivity of the hypothalamic-pituitary-adrenal (HPA) axis are often seen in depression, implicating HPA axis dysfunction as a potentially causative or exacerbating factor. Chronic stress is also a factor in depression, but it is not known what may underlie the shift from adaptive to maladaptive HPA activity over the course of chronic stress. Interleukin 6 (IL-6), a stress-inducible cytokine that signals through gp130 and IL-6Rα receptors to activate the JAK/STAT3 signaling cascade, is elevated in some subtypes of depression, and may have a modulatory effect on HPA activation, raising the possibility that IL-6 contributes to depression through effects on the HPA axis. In this study, we examined the effects of three different stress modalities, acute footshock, chronic intermittent cold (CIC) stress and chronic unpredictable stress (CUS) on IL-6 signaling in the hypothalamus. We also investigated whether IL-6 modulates the HPA response to chronic stress, by blocking IL-6 signaling in the brain during CIC stress using either a neutralizing antibody or an inhibitor of STAT3 phosphorylation. We show that IL-6 and STAT3 in the hypothalamus are activated in response to footshock and CUS. We also found that basal IL-6 signaling through the JAK/STAT3 pathway is required for the sustained CORT response to chronic, but not acute, cold stress and therefore is a potential determinant of plasticity in the HPA axis specifically during chronic stress exposure.

Sigma receptor antagonists attenuate acute methamphetamine-induced hyperthermia by a mechanism independent of IL-1β mRNA expression in the hypothalamus

Methamphetamine is currently one of the most widely abused drugs worldwide, with hyperthermia being a leading cause of death in methamphetamine overdose situations. Methamphetamine-induced hyperthermia involves a variety of cellular mechanisms, including increases in hypothalamic interleukin-1 beta (IL-1β) expression. Methamphetamine also interacts with sigma receptors and previous studies have shown that sigma receptor antagonists mitigate many of the behavioral and physiological effects of methamphetamine, including hyperthermia. The purpose of the current study was to determine if the attenuation of methamphetamine-induced hyperthermia by the sigma receptor antagonists, AZ66 and SN79, is associated with a concomitant attenuation of IL-1β mRNA expression, particularly in the hypothalamus. Methamphetamine produced dose- and time-dependent increases in core body temperature and IL-1β mRNA expression in the hypothalamus, striatum, and cortex in male, Swiss Webster mice. Pretreatment with the sigma receptor antagonists, AZ66 and SN79, significantly attenuated methamphetamine-induced hyperthermia, but further potentiated IL-1β mRNA in the mouse hypothalamus when compared to animals treated with methamphetamine alone. These findings suggest sigma receptor antagonists attenuate methamphetamine-induced hyperthermia through a different mechanism from that involved in the modulation of hypothalamic IL-1β mRNA expression.

An in vivo animal study assessing long-term changes in hypothalamic cytokines following perinatal exposure to a chemical mixture based on Arctic maternal body burden.

BackgroundThe geographic distribution of environmental toxins is generally not uniform, with certain northern regions showing a particularly high concentration of pesticides, heavy metals and persistent organic pollutants. For instance, Northern Canadians are exposed to high levels of persistent organic pollutants like polychlorinated biphenyls (PCB), organochlorine pesticides (OCs) and methylmercury (MeHg), primarily through country foods. Previous studies have reported associations between neuronal pathology and exposure to such toxins. The present investigation assessed whether perinatal exposure (gestation and lactation) of rats to a chemical mixture (27 constituents comprised of PCBs, OCs and MeHg) based on Arctic maternal exposure profiles at concentrations near human exposure levels, would affect brain levels of several inflammatory cytokinesMethodsRats were dosed during gestation and lactation and cytokine levels were measured in the brains of offspring at five months of age. Hypothalamic cytokine protein levels were measured with a suspension-based array system and differences were determined using ANOVA and post hoc statistical tests.ResultsThe early life PCB treatment alone significantly elevated hypothalamic interleukin-6 (IL-6) levels in rats at five months of age to a degree comparable to that of the entire chemical mixture. Similarly, the full mixture (and to a lesser degree PCBs alone) elevated levels of the pro-inflammatory cytokine, IL-1b, as well as the anti-inflammatory cytokine, IL-10. The full mixture of chemicals also moderately increased (in an additive fashion) hypothalamic levels of the pro-inflammatory cytokines, IL-12 and tumor necrosis factor (TNF-α). Challenge with bacterial endotoxin at adulthood generally increased hypothalamic levels to such a degree that differences between the perinatally treated chemical groups were no longer detectable.ConclusionsThese data suggest that exposure at critical neurodevelopmental times to environmental chemicals at concentrations and combinations reflective of those observed in vulnerable population can have enduring consequences upon cytokines that are thought to contribute to a range of pathological states. In particular, such protracted alterations in the cytokine balance within the hypothalamus would be expected to favor marked changes in neuro-immune and hormonal communication that could have profound behavioral consequences.

Social status modulates basal IL-1 concentrations in the hypothalamus of pair-housed rats and influences certain features of stress reactivity

Recent findings from our laboratory and others indicate that exposure to stress can increase expression of the pro-inflammatory cytokine interleukin-1 (IL-1). In a series of studies examining this response, we observed pronounced differences in baseline levels of hypothalamic IL-1 of pair-housed rats. We hypothesized that these pair-wise differences might be a result of prolonged social stress associated with dominance/submissiveness, and that the submissive animal would show heightened baseline levels of IL-1. In order to test this hypothesis, we utilized a food competition paradigm (access to cheerios) to assess dominance within a dyad prior to the assessment of hypothalamic IL-1 levels. Based on the results of this test, clear dominance hierarchies were observed in ∼50% of the dyads, a ratio comparable to what has been reported previously. More importantly, this dominant/submissive categorization could be used to predict pair-wise differences in hypothalamic IL-1 with greater than 90% accuracy. Specifically, the submissive rat in each dyad (determined a priori) consistently evinced hypothalamic IL-1 levels that were nearly double that of its dominant cage mate. Further studies demonstrated that submissive rats showed a more rapid and pronounced hyperthermic response to novel environment stress relative to dominant rats. Interestingly, social status had no effect on corticosterone reactivity, even when the nature and intensity of the stressor was varied. Finally, maintenance of a clear dominance hierarchy obfuscated hypothalamic IL-1 responses to footshock exposure, with the most robust increases in hypothalamic IL-1 provoked by footshock being observed in pairs where there was no clear dominance hierarchy. Together, these findings suggest that social status can have a significant impact on stress reactivity and neuroimmune consequences of stressor exposure even in the unperturbed home cage environment.

Central interleukin-1 (IL1) signaling is required for pharmacological, but not physiological, effects of leptin on energy balance

Hypothalamic IL1 is suggested to be a critical mediator of the central effects of the adipocyte hormone leptin on energy balance. We hypothesized that IL1 receptor signaling is required for exogenously administered leptin to cause anorexia and weight loss, but not for physiological effects of endogenous leptin signaling on energy balance. To test this hypothesis, we investigated whether chronic hypothalamic over-expression of an IL1 receptor antagonist (AdV-IL1ra) alters food intake and weight gain in normal rats. Our findings demonstrate that impaired IL1 signaling in the CNS did not cause excess weight gain over a period of 11 days (AdV-IL1ra + 38.1 ± 4.1 g vs. VEH + 42.2 ± 5.6g; p = 0.6) and caused a slightly reduced daily food intake (AdV-IL1ra 29.0 ± 1.1 g/day vs. VEH 33.0 ± 1.6 g/day; p < 0.05). Blocking central IL1 signaling also did not alter the re-feeding response to a prolonged fast, yet was entirely effective in preventing the anorexic effect of exogenously administered leptin (2 mg/kg ip, cumulative food intake at 18 h AdV-IL1ra 30.5 ± 1.1 g vs. VEH 26.4 ± 1.7 g, p < 0.05) and prevented leptin-induced weight loss (AdV-IL1ra − 0.1 ± 1.3 g vs. VEH − 2.7 ± 1.9 g, p < 0.05). Together these findings suggest that hypothalamic IL1 signaling is required for the pharmacological effects of leptin administration, but that impaired hypothalamic IL1 signaling does not alter the physiological regulation of energy balance.

Social interactions alter proinflammatory cytokine gene expression and behavior following endotoxin administration

Sick animals display a constellation of behaviors, including anhedonia, anorexia, and reduced social interactions. Acute infection eliminates female mating behavior, but fails to attenuate mating behavior in male rats. These results have been attributed to the different reproductive strategies and parental investment of the two sexes. Males putatively suppress the symptoms of infection in order to “deceive” females into mating. We sought to investigate the mechanisms responsible for this suppression. Adult male CD-1 mice were treated with lipopolysaccharide (LPS; a component of bacterial cell walls; 400 μg/kg), then paired 2 h later with a receptive female or juvenile male or remained isolated. Blood samples and brains of the males were collected 3 h post-LPS; hypothalamic interleukin-1 ( IL- 1) and tumor necrosis factor-α ( TNFα) gene expression was measured using RT-PCR. Contrary to our prediction, exposure to a female increased hypothalamic IL- 1 and TNFα gene expression. LPS treatment significantly decreased testosterone and increased corticosterone secretions. Social interactions altered absolute corticosterone concentrations in saline-injected animals only. In order to determine whether increased production of hypothalamic cytokines reflected increased severity of sickness responses, body temperature was monitored in a second group of mice implanted with telemetric transmitters. Body mass, food intake, and consumption of sweetened condensed milk (a highly favored food) were also monitored in these mice for 72 h post-injection. LPS injections reduced milk intake, an effect that was modulated by social interactions; however, fever was unaltered relative to isolated animals. These results suggest that social interactions can adjust behavioral responses to infection although the ultimate cause of this adjustment remains unspecified.

Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats

Interleukin-6 (IL-6) is a multifunctional cytokine that may have a role in energy regulation. Using a recombinant adeno-associated viral vector expressing murine interleukin-6 (rAAV-IL-6), we examined the chronic effects of centrally expressed IL-6 on food intake, body weight and adiposity in male Sprague–Dawley rats, and investigated the underlying mechanisms. Direct delivery of rAAV-IL-6 into rat hypothalamus suppressed weight gain and visceral adiposity without affecting food intake over a 5-week period. rAAV-IL-6 enhanced uncoupling protein 1 (UCP1) protein levels in interscapular brown adipose tissue (BAT). To investigate if the induction of UCP1 and the reduction in body weight are dependent on sympathetic innervation of BAT, we administered rAAV-IL-6 or a control vector into the hypothalamus of rats in which the interscapular BAT was unilaterally denervated. Over 21 days, there was no difference in food consumption or body weight between rAAV-IL-6- and control vector-treated rats. rAAV-IL-6 delivery increased UCP1 mRNA and protein levels in innervated BAT pads but not denervated BAT pads. Hypothalamic IL-6 signal transduction, indicated by phosphorylated signal transducer and activator of transcription 3 (P-STAT3) levels, was elevated by 2.6-fold at day 21, but returned to control levels by day 35. However, the suppressor of cytokine signaling-3 mRNA level was significantly elevated both at day 21 and day 35. These data demonstrate that chronic elevation of IL-6 in the CNS reduces body weight gain and visceral adiposity without affecting food intake. The mechanism involves sympathetic induction of UCP1 in BAT and, presumably, enhanced thermogenesis in BAT. Furthermore, chronic central IL-6 stimulation desensitizes IL-6 signal transduction characterized by reversal of elevated P-STAT3 levels.

Local inhibition of LPS-induced hypothalamic TNF-formation by pentoxifylline has no effect on production of IL-6 within the anterior hypothalamus

Push–pull perfusions of the anterior hypothalamus were performed in four groups of guinea pigs characterized as follows: (a) hypothalamus perfused with artificial cerebrospinal fluid (CSF), intramuscular (im) injection of 20 μg/kg bacterial lipopolysaccharide (LPS); (b) hypothalamus perfused with CSF, im injection of saline; (c) hypothalamus perfused with CSF which contained 0.1 μg/μl pentoxifylline, im injection of LPS; (d) hypothalamus perfused with CSF which contained 0.1 μg/μl pentoxifylline, im injection of saline. Injection of LPS resulted in a significant rise of hypothalamic tumor necrosis factor-α (TNF), 60 min and 180 min after administration of LPS compared to the value measured 60 min before LPS was injected. In animals injected with saline, the baseline level of TNF in hypothalamic perfusates remained manifest. Perfusion of the anterior hypothalamus with CSF which contained 0.1 μg/μl pentoxifylline resulted in a complete suppression of hypothalamic TNF formation and release in animals injected with LPS or saline. The LPS-induced rise of hypothalamic interleukin-6 (IL-6) was the same in guinea-pigs perfused with CSF or CSF plus pentoxifylline. The LPS-induced rise of rectal temperature, measured about 3 h after LPS injection (fever peak) was the same in guinea-pigs perfused with CSF or CSF plus pentoxifylline. The results indicate that the hypothalamic rise of IL-6 and the febrile temperature peak in response to peripheral injection of LPS does not depend on the local formation of TNF within the anterior hypothalamus.

Hypothalamic interleukin-1 in physiology and pathology

The occurrence of interleukin-1 (IL-1) in the brain is usually associated with pathological events of the central nervous system (CNS), although there is evidence that the cytokine may also play a role in physiological processes. The ability of IL-1 to induce a damage in the CNS is dependent on the type of cell producing the cytokine and the length of exposure; on this regard, it is possible to distinguish between the minutes-to-days and the days-to-years time-frames. While the long-term action of IL-1 in the CNS is unambiguously associated with the activation of glial cells as well as the occurrence of chronic disorders such as Alzheimer's disease and AIDS-related dementia, it remains to be established whether glial cells, `interleukinergic' neurons or both cell types are involved in CNS responses to acute noxiae, such as physical stress (restrain stress, nociceptive stimulation) or immune-inflammatory challenges.

Anterior hypothalamic interleukin-1 receptors are involved in mediation of fever during bacterial sepsis in rats.

Anterior hypothalamic interleukin-1 receptors are involved in mediation of fever during bacterial sepsis in rats.

Involvement of interleukin-1 in immobilization stress-induced increase in plasma adrenocorticotropic hormone and in release of hypothalamic monoamines in the rat

We investigated whether interleukin-1 (IL-1) activity in the rat hypothalamus was increased by immobilization stress (IS), and whether pretreatment with an interleukin-1 receptor antagonist (IL-1Ra) is capable of inhibiting IS-induced elevations of hypothalamic norepinephrine (NE), dopamine (DA), and serotonin (5-HT) and the levels of their metabolites as well as of plasma adrenocorticotropic hormone (ACTH). IL-1 activity was estimated with a bioassay using mouse thymocyte proliferation in the presence of concanavalin A. IL-1Ra was administered directly into the anterior hypothalamus, and monoamines were determined using a microdialysis technique and an HPLC system. First, we found that levels of IL-1 activity in the rat hypothalamus reached a maximum at 60 min after starting IS. Second, IL-1Ra (2 micrograms) significantly inhibited IS-induced increases in hypothalamic NE, DA, and 5-HT levels as well as the levels of their metabolites. In addition, IL-1Ra (2 micrograms) also inhibited the IS-induced elevation of plasma ACTH levels. Third, timing effects of IL-1Ra administration on the IS-induced monoamines or ACTH responses were examined. IL-1Ra (2 micrograms) administered at 5 or 60 min before the start of IS, but not at 5 or 60 min after IS had been started, exerted inhibitory effects on these responses, indicating that the effects of IL-1 occurred within 5 min after the initiation of IS. In summary, these results suggest that IS enhances biologically active IL-1 in the hypothalamus, and that hypothalamic IL-1 plays a role in the regulation of IS-induced responses including elevated monoamine release in the hypothalamus and activation of the hypothalamo-pituitary-adrenal axis. Moreover, since 5 min is too short a time for IS to induce production of IL-1, IS may augment the effects of preexisting IL-1 in the hypothalamus.

Roles of Interleukin-1 Receptor on Stress-induced Increase in Monamine Release and ACTH Secretion in the Rat.

We investigated whether pretreatment with an interleukin-1 receptor antagonist (IL-1RA) is capable of inhibiting immobilization stress (IS) -induced elevations of hypothalamic norepinephrine (NE) and the levels of their metabolites as well as the plasma adrenocorticotropic hormone (ACTH) . IL-1 RA was administered directly into the anterior hypothalamus, and monoamines were determined using a microdialysis technique and an HPLC system. IL-1 RA (2μg) significantly inhibited IS-induced increases in hypothalamic NE level. In addition, IL-1RA (2μg) also inhibited the IS-induced elevation of plasma ACTH levels. In summary, these results suggest that hypothalamic interleukin-1 (IL-1) plays a role in the regulation of IS-induced responses including elevated monoamine release in the hypothalamus and activation of the hypothalamo-pituitary-adrenal axis.