Administration Of Interleukin-1β Research Articles

Exercise induced meteorin-like protects chondrocytes against inflammation and pyroptosis in osteoarthritis by inhibiting PI3K/Akt/NF-κB and NLRP3/caspase-1/GSDMD signaling

The production of metrnl, a novel adipomyokine, is induced upon exercise in adipose tissue and skeletal muscle. In this study, we investigated the anti-inflammatory and antipyroptotic effects of exercise-induced metrnl producted in rats in vitro and in vivo. Forty Sprague-Dawley rats were divided randomly into five groups: control (CG), osteoarthritis (OA) with sedentary lifestyle (OAG), OA with low intensity exercise (OAL), OA with moderate intensity exercise (OAM), and OA with high intensity exercise (OAH). The correlation between the level of metrnl and OA degree was detected using ELISA, X-ray imaging, histology, and immunohistochemistry in vivo. Primary chondrocytes were preincubated with recombinant metrnl before interleukin-1β administration to verify the anti-inflammatory and antipyroptotic effects of metrnl. Western blotting and quantitative reverse transcription (qRT)-PCR were used to evaluate the differences in protein and mRNA expression between groups, respectively. Reactive oxygen species (ROS) assay, immunofluorescence, transmission electron microscopy (TEM), and flow cytometry were used to evaluate morphological changes and pyroptosis in chondrocytes. In the moderate-intensity treadmill exercise group, the severity of OA showed maximum relief and the metrnl levels had the most significant increase. Metrnl exerted its anti-inflammatory effect through the suppression of the PI3K/Akt/NF-κB pathway in IL-1β-induced OA chondrocytes, which was accompanied with the recovery of collagen II expression and the attenuation of MMP13 and ADAMTS5. Moreover, metrnl ameliorated chondrocyte pyroptosis by inhibiting the activation of the nod-like receptor protein-3/caspase-1/gasdermin D cascade. In conclusion, moderate-intensity exercise improves inflammation and pyroptosis by increasing metrnl release, which inhibits the PI3K/Akt/NF-κB and further NLRP3/caspase-1/GSDMD signaling pathways.

Interleukin-10 Attenuates Behavioral, Immune and Neurotrophin Changes Induced by Chronic Central Administration of Interleukin-1β in Rats

Background: Activated microglia can trigger pro-inflammatory cytokine releases and neuroinflammation, which may inhibit astrocytes to produce neurotrophins and anti-inflammatory factors. Both eventually lead to neuron apoptosis or death. Furthermore, effective antidepressant or anti-dementia treatments can reduce pro-inflammatory cytokines, while enhance interleukin (IL)-10 production. However, the underline mechanism by which IL-10 modulates glial cell function, hence improves cognitive impairment or depression-like behavior is unknown. This study evaluated whether and how IL-10 attenuated chronic IL-1β administration-induced behavioral changes and the possible involved mechanisms. Methods: Rats received intracerebroventricular injection of IL-1β and/or IL-10 for 14 days. Then animal memory and depression-like behavior, pro-inflammatory cytokines, glial activities, expression of brain-derived neurotrophic factor (BDNF), Trk B, p75, and apoptosis-related genes were studied. Results: Compared to controls, significantly increased latent time and swimming distance in the Morris-water-maze, decreased sucrose consumption, and decreased locomotor and center zone entries in the open-field were found in rats administrated with IL-1β. These changes were associated with the reduction of GFAP expression, and concentrations of BDNF and anti-inflammatory cytokine IL-10, but the increase in the expressions of CD11b, TrkB, p75, and Caspase-3, the ratio of Bax/Bcl-2, and the concentrations of IL-1β, tumor necrosis factor-α, and IL-6. IL-10 treatment markedly attenuated IL-1β-induced above changes, except for the expressions of neurotrophin receptors. Conclusion: IL-10-improved behavioral changes may be through suppressing microglia activity and inflammation, while restoring astrocyte function and BDNF expression.

IL‐1β‐Induced Thermoregulation and Vagus Nerve Activity is Mediated by Transient Receptor Potential Ankyrin 1

Intraperitoneal administration of interleukin-1β (IL-1β), a cytokine mediator of inflammation and injury, induces afferent vagus nerve signaling and brain-mediated sickness syndrome. However, the mechanism of IL-1β signaling through the vagus nerve is unknown. Here we show that transient receptor potential ankyrin 1 (TRPA1) expression in sensory vagus neurons is required to mediateIL-1β-induced thermoregulation and vagus nerve activation. We monitored body temperature in conscious and unrestrained mice by radiotelemetry using probes implanted into peritoneal cavity. Intraperitoneal administration of IL-1β induced a significant change in body temperature in wild type mice. However, this response was significantly impaired in TRPA1 knock out mice (TRPA1 KO) (wild type vs. TRPA1 KO; 1045 ± 35.29 AUC vs. 577.9 ± 26.13 AUC; t-test with Welch's correction; p<0.0001). To investigate whether selective TRPA1 expression in neurons is required for IL-1β-induced thermoregulation, we generated Syn-Cre/TRPA1fl/fl mice selectively devoid of TRPA1 expression in neurons. Selective ablation of TRPA1-expression in neurons significantly attenuates IL-1β-induced changes in body temperature (wild type vs. Syn-Cre/TRPA1fl/fl; 1082 ± 61.49 AUC vs. 775.8 ± 66.89 AUC; t-test with Welch's correction; p<0.01). We have previously shown IL-1β induces sensory signaling by recording vagus nerve activity. Accordingly, here we collected extra-neural recordings from the cervical vagus nerve and as expected observed administration of IL-1β induced a significant increase in vagus nerve activity (total spikes 5 minutes pre- and post-administration: 85.6 ± 0.17 spikes vs. 9998.0 ± 3617.0 spikes; t-test; p<0.01). Moreover, no significant changes in vagus nerve activity occurred in TRPA1 KO mice (pre vs post-administration: 867.3 ± 395.7 spikes vs. 1069.0 ± 455.8 spikes, t-test, N.S.), and in Syn-Cre/TRPA1fl/fl mice (pre vs post-administration: 2179.0 ± 558.8 spikes vs. 1996.0 ± 460.8 spikes; t-test; N.S.). Whole-cell patch-clamp recordings and calcium imaging revealed TRPA1 is required to mediate IL-1β-dependent activation of vagus sensory neurons. Together, these studies indicate IL-1β-induced thermoregulation and vagus nerve activation is mediated by TRPA1.

Mifepristone attenuates depression-like changes induced by chronic central administration of interleukin-1β in rats

Increased proinflammatory cytokines, such as interleukin (IL)-1β, may play an important role in the etiology of depression because they cause the hypothalamic–pituitary–adrenal axis to release glucocorticoids (GC) and induce dysfunction of serotonin and norepinephrine neurotransmission. Sustained increase in GC may activate microglia to induce neuroinflammation, and suppress astrocytes to produce neurotrophins, which lead to neuronal apoptosis. Here, we tested the hypothesis that glucocorticoid receptor (GR) antagonist mifepristone (RU486) may attenuate IL-1β-induced depression-like behavior by regulating the neuroinflammation and neurotrophin functions of microglia and astrocytes. Rats received intracerebroventricular injections of IL-1β (10 ng) and/or subcutaneous injections of RU486 for 14 days. Then animal depression-like behaviors, serum corticosterone concentration, the levels of pro-inflammatory cytokines (TNF-α, IL-6), mRNA and protein expressions of CD11b, GFAP and neurotrophins (pro-BDNF, BDNF, GDNF and their receptors TrkB, p75, GFRα-1 and GFRα-2) in the amygdala were studied. Compared to controls, significantly decreased rearing score and increased defecation in the open field test, decreases in ratio of open/closed time in the elevated plus maze and in sucrose preference, while increased level of corticosterone in the serum were found in the rats administrated with IL-1β. IL-1β administration also reduced the expressions of GFAP, BDNF, GDNF and its receptor GFR-α1, but increased the expressions of CD11b, pro-BDNF, p75 and pro-inflammatory cytokines (TNF-α, IL-6) concentrations. RU486 treatment markedly attenuated these changes induced by IL-1β, except for the expressions of GFR-α1. In conclusion, RU486 may improve depression-like changes by suppressing microglia and inflammation and promoting astrocytes to restore neurotrophin function.

Fetal skin as a pro-inflammatory organ: Evidence from a primate model of chorioamnionitis.

BackgroundIntrauterine infection is a primary cause of preterm birth and fetal injury. The pro-inflammatory role of the fetal skin in the setting of intrauterine infection remains poorly characterized. Whether or not inflammation of the fetal skin occurs in primates remains unstudied. Accordingly, we hypothesized that: i) the fetal primate skin would mount a pro-inflammatory response to preterm birth associated pro-inflammatory agents (lipopolysaccharides from Escherichia coli, live Ureaplasma parvum, interleukin-1β) and; ii) that inhibiting interleukin-1 signaling would decrease the skin inflammatory response.MethodsRhesus macaques with singleton pregnancies received intraamniotic injections of either sterile saline (control) or one of three pro-inflammatory agonists: E. coli lipopolysaccharides, interluekin-1β or live U. parvum under ultrasound guidance. A fourth group of animals received both E. coli lipopolysaccharide and interleukin-1 signaling inhibitor interleukin-1 receptor antagonist (Anakinra) prior to delivery. Animals were surgically delivered at approximately 130 days’ gestational age.ResultsIntraamniotic lipopolysaccharide caused an inflammatory skin response characterized by increases in interluekin-1β,-6 and -8 mRNA at 16 hours. There was a modest inflammatory response to U. parvum, but interleukin-1β alone caused no inflammatory response in the fetal skin. Intraamniotic Anakinra treatment of lipopolysaccharide-exposed animals significantly reduced skin inflammation.ConclusionsIntraamniotic lipopolysaccharide and U. parvum were associated with modest increases in the expression of inflammatory mediators in primate fetal skin. Although administration of Interleukin-1β alone did not elicit an inflammatory response, lipopolysaccharide-driven skin inflammation was decreased following intraamniotic Anakinra therapy. These findings provide support for the role of the fetal skin in the development of the fetal inflammatory response.

Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants

Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1β administration, we undertake gene network analysis of the microglial transcriptomic response to injury, extend this by analysis of protein-protein interactions, transcription factors and human brain gene expression, and translate findings to living infants using imaging genomics. We show that DLG4 (PSD95) protein is synthesised by microglia in immature mouse and human, developmentally regulated, and modulated by inflammation; DLG4 is a hub protein in the microglial inflammatory response; and genetic variation in DLG4 is associated with structural differences in the preterm infant brain. DLG4 is thus apparently involved in brain development and impacts inter-individual susceptibility to injury after preterm birth.

Dietary eicosapentaenoic acid normalizes hippocampal omega-3 and 6 polyunsaturated fatty acid profile, attenuates glial activation and regulates BDNF function in a rodent model of neuroinflammation induced by central interleukin-1β administration

Interleukin (IL)-1β can activate glial cells to trigger neuroinflammation and neurodegeneration. Lower omega (n)-3 polyunsaturated fatty acids (PUFAs) and lower n-3/n-6 PUFA ratios occur in the brain of patients with Alzheimer's disease (AD). We have previously reported that an n-3 PUFA, eicosapentaenoic acid (EPA), can improve memory and attenuate neurodegeneration-like changes in animal models of AD. However, whether and how EPA modulates glial cell activity and functions remains unclear. The aim of this study was to test the hypothesis that EPA may attenuate neuroinflammation by inhibiting microglial activation and microglia-produced proinflammatory cytokines, and by enhancing the expression of astrocytes-produced neurotrophins and their receptors. Male Long-Evans rats were fed either palm oil supplemented diet or EPA supplemented diet for 42days. On day 36 of diet feeding, rats received an intracerebroventricular injection of IL-1β or saline for 7days. The glial activation, the expression of amyloid precursor protein (APP), calcium-dependent phospholipase (cPL) A2, brain-derived neurotrophic factor (BDNF) and its receptor, and PUFA profile in the hippocampus were analyzed. IL-1β elevated biomarkers of microglial CD11b and astrocyte GFAP expression, increased the expression of APP, tumor-necrosis factor (TNF)-α, but reduced BDNF and its receptor (TrKB). IL-1β also lowered n-3 EPA and docosapentaenoic acid concentrations but increased n-6 PUFAs and cPLA2 activity in the hippocampus. EPA supplement normalized the n-3 and n-6 PUFA profiles and cPLA2 levels, inhibited glial activation, reduced APP and TNF-α expression, as well as up-regulated BDNF and TrKB. Supplementation with EPA appear to have potential effects on improving glial over-activation, n3/n6 imbalance and BDNF down-regulation, which contribute to anti-inflammatory and may provide beneficial effects on inflammation-associated disease such as AD.

The Course of Experimental Allergic Encephalomyelitis in Adult Rats after Administration of Interleukin-1β at Different Periods in Early Life

Multiple sclerosis (MS) is a chronic disease of the CNS affecting people of working age, in which myelin and the cells producing it, and also neurons, become the targets for aggressive immune cells. It has been suggested that common childhood infections in later childhood increase the risk of developing MS. We report here studies of the course of experimental allergic encephalomyelitis (EAE) in rats given interleukin-1β (IL-1β) at different stages of early postnatal ontogeny. EAE was induced in rats at age three months by single subcutaneous immunizations with homologous spinal cord homogenate in complete Freund’s adjuvant. The number of sick animals was recorded daily, as were the severity and duration of disease. EAE was found to have a more severe course after administration of IL-1β in weeks 1 and 4 of life than in rats of the corresponding control groups. The harmful or protective consequences of IL-1β administration at different periods of early postnatal ontogeny are discussed, as are the role of stress reactivity and its link with the “hygiene hypothesis.”

Expression of the FGF2 and TIMP1 Genes in the Adult Rat Brain after Administration of Interleukin-1β during Early Postnatal Ontogeny

Hypotheses relating to the developmental nature of cognitive impairments in schizophrenia and other neuropathologies propose that the development of stable cognitive deficit involves important roles for hypoxia, trauma, and infections operating during the prenatal and early postnatal periods. These pathological states are accompanied by increases in the production of proinflammatory cytokine interleukin-1β (IL-1β) in cells of the nervous and immune systems. We report here studies of the characteristics of the expression of the Fgf1 and Timp1 genes, which are involved in regulating the cerebral mechanisms of neuroplasticity, in cells of the medial prefrontal cortex and the dorsal and ventral areas of the hippocampus in adult rats given IL-1β during early postnatal ontogeny. Experiments were performed in standard conditions and on acquisition of a conditioned active avoidance reflex. Learning impairments in experimental animals were accompanied by decreased production of FGF-2 mRNA in cells of the medial prefrontal cortex and ventral hippocampus. There were no differences between groups in conditions without cognitive loading.

Selective contributions of neuronal and astroglial interleukin-1 receptor 1 to the regulation of sleep.

Interactions between sleep and immune function are bidirectional. Although the mechanisms that govern these interactions are not fully elucidated, the pro-inflammatory cytokine, interleukin-1β (IL-1), is a known regulator of sleep and mediator of immune responses. To further clarify the underlying substrates of sleep and immune interactions, we engineered two transgenic mouse lines that express interleukin-1 receptor 1 (IL1R1) only in the central nervous system (CNS) and selectively on neurons (NSE-IL1R1) or astrocytes (GFAP-IL1R1). During spontaneous sleep, compared to wild type (WT) animals, NSE-IL1R1 and GFAP-IL1R1 mice have more rapid eye movement sleep (REMS) that is characterized by reduced theta power in the electroencephalogram (EEG) spectra. The non-REM sleep (NREMS) EEG of each of the IL1R1 transgenic mouse strains also is characterized by enhanced power in the delta frequency band. In response to 6h of sleep deprivation, sleep of both IL1R1 transgenic mouse strains is more consolidated than that of WT animals. Additionally, the NREMS EEG of NSE-IL1R1 mice contains less delta power after sleep deprivation, suggesting astroglial IL1R1 activity may modulate sleep homeostasis. Intracerebroventricular injection of IL-1 fails to alter sleep or brain temperature of NSE-IL1R1 or GFAP-IL1R1 mice. These data suggest that selective IL1R1 expression on neurons or on astrocytes is not sufficient for centrally-administered IL-1 to induce sleep or fever. Lack of sleep and febrile responses to IL-1 in these IL1R1 transgenic mouse strains may be due to their inability to produce IL-6 in brain. Overall, these studies demonstrate, through the use of novel transgenic mice, that IL1R1 on neurons and astrocytes differentially mediates aspects of sleep under physiological conditions and in response to central IL-1 administration.

L-arginine abolishes the hypothalamic serotonergic activation induced by central interleukin-1β administration to normal rats

IL-1β-induced anorexia may depend on interactions of the cytokine with neuropeptides and neurotransmitters of the central nervous system control of energy balance and serotonin is likely to be one catabolic mediator targeted by IL-1β. In the complex interplay involved in feeding modulation, nitric oxide has been ascribed a stimulatory action, which could be of significance in counteracting IL-1β effects.The present study aims to explore the participation of the nitric oxide and the serotonin systems on the central mechanisms induced by IL-1β and the relevance of their putative interactions to IL-1β hypophagia in normal rats.Serotonin levels were determined in microdialysates of the ventromedial hypothalamus after a single intracerebroventricular injection of 10 ng of IL-1β , with or without the pre-injection of 20 μg of the nitric oxide precursor L-arginine. IL-1β significantly stimulated hypothalamic serotonin extracellular levels, with a peak variation of 130 ±37% above baseline. IL- 1β also reduced the 4-h and the 24-h food intakes (by 23% and 58%, respectively). The IL-1β-induced serotonergic activation was abolished by the pre-injection of L-arginine while the hypophagic effect was unaffected.The data showed that one central effect of IL-1β is serotonergic stimulation in the ventromedial hypothalamus, an action inhibited by nitric oxide activity. It is suggested that, although serotonin participates in IL-1β anorexia, other mechanisms recruited by IL-1β in normal rats are able to override the absence of the serotonergic hypophagic influence.

Nerve injury-induced upregulation of miR-21 in the primary sensory neurons contributes to neuropathic pain in rats

Neuropathic pain is intractable chronic pain caused by damage to the somatosensory system. Peripheral nerve injury of the primary sensory neurons changes expressions of multiple microRNAs that affect many aspects of cellular functions by regulating specific gene expressions. miR-21, a well-characterized oncogenic miRNA, is consistently upregulated after peripheral nerve injury in the dorsal root ganglion (DRG), where cell bodies of primary sensory neurons exist. However, their causal relationship to the pain is fully unknown. In this study, we therefore investigated the miR-21 expression in the DRGs along with the time course of neuropathic pain and its involvement in the neuropathic pain. Neuropathic pain was induced in rats by specific ligation of the left fifth lumbar spinal nerve. After the injury, miR-21 expression in the injured DRG neurons, but not in the neighboring uninjured DRG neurons, was persistently upregulated following the pain development. Intrathecal administration of interleukin-1β also increased the miR-21 expression in the DRG. Both mechanical allodynia and thermal hyperalgesia in the neuropathic pain were attenuated by intrathecal administration of miR-21 inhibitor. miR-21 is specifically upregulated in the injured DRG neurons and causally involved in the late phase of neuropathic pain. Therefore, miR-21 and its modulatory system may be a therapeutic target for intractable chronic neuropathic pain.

P.1.014 Intracerebroventricular administration of interleukin-1β elevates brain kynurenic acid and disrupts prepulse inhibition in C57BL/6 mice

Olfactory bulbectomy (OBX) is a well known screening model for depression. Panax quinquefolium (PQ) is known for its therapeutic potential against several psychiatric disorders. Nitric oxide (NO), an intercellular messenger has been suggested to play a crucial role in the pathogenesis of depression. The present study was designed to explore the possible involvement of NO mechanism in the protective effect of PQ against olfactory bulbectomy induced depression. Wistar rats were bulbectomized surgically and kept for a rehabilitation period of two weeks. PQ (50, 100 and 200 mg/kg; p.o.) alone and in combination with NO modulators like l-NAME (10 mg/kg, i.p.) and l-arginine (100 mg/kg; i.p.) were then administered daily for another two weeks. Ablation of olfactory bulbs caused depression-like symptoms as evidenced by increased immobility time in forced swim test, hyperactivity in open field arena, and anhedonic like response in sucrose preference test. Further, OBX caused elevation in serum corticosterone levels and increased oxidative–nitrosative damage. These deficits were integrated with increased levels of neuroinflammatory cytokines (TNF-α), apoptotic factor (caspase-3) and a marked reduction in neurogenesis factor (BDNF) in both cerebral cortex and hippocampal regions of bulbectomized rats. Treatment with PQ significantly and dose-dependently restored these behavioral, biochemical and molecular alterations associated with OBX. Further, pretreatment of l-NAME with subeffective dose of PQ (100 mg/kg) significantly potentiated its protective effects; however l-arginine pretreatment reversed the beneficial effects. The present study suggests that protective effect of P. quinquefolium might involve nitric oxide modulatory pathway against olfactory bulbectomy-induced depression in rats.

Impairments to Conditioned Reflex Activity in Adult Rats after Administration of Interleukin-1β during Early Postnatal Ontogeny

Impairments to cognitive functions in children and adolescents often result from a variety of types of prenatal pathology (birth traumas, ischemia, hypoxia, and allergic and infectious diseases in early life) accompanied by high levels of production of the proinflammatory cytokine interleukin-1β. The studies reported here identified impairments to the acquisition of conditioned active and passive reflex avoidance reactions in adult animals given interleukin-1β during the third week of life.

Inhibitory Function of the Dorsomedial Hypothalamic Nucleus on the Hypothalamic–Pituitary–Adrenal Axis Response to an Emotional Stressor but not Immune Challenge

Accumulating evidence implicates the dorsomedial hypothalamic nucleus (DMH) in the regulation of autonomic and neuroendocrine stress responses. However, although projections from the DMH to the paraventricular hypothalamic nucleus (PVN), which is the critical site of the neuroendocrine stress axis, have been described, the impact of DMH neurones in the modulation of hypothalamic-pituitary-adrenal (HPA) axis activation during stress is not fully understood. The present study aimed to investigate the role of the DMH in HPA axis responses to different types of stimuli. Male Sprague–Dawley rats fitted with a chronic jugular venous catheter were exposed to either an emotional stressor (elevated platform-exposure) or immune challenge (systemic interleukin-1β administration). Bilateral electrolytic lesions of the DMH disinhibited HPA axis responses to the emotional stressor, as indicated by higher plasma adrenocorticotrophic hormone levels during and after elevated platform exposure in lesioned animals compared to sham-lesioned controls. Moreover, DMH-lesioned animals showed increased neuronal activation in the PVN, as indicated by a higher c-Fos expression after elevated-platform exposure compared to controls. By contrast, DMH-lesions had no effects on HPA axis responses to immune challenge. Taken together, our data suggest an inhibitory role of DMH neurones on stress-induced HPA axis activation that is dependent upon the nature of the stimulus being important in response to an emotional stressor but not to immune challenge.

Antioxidant Protection of the Brain in Rats during Acute Stress and Administration of Interleukin-1β

We studied the effect of IL-1β on antioxidant enzyme activity in emotiogenic structures of the brain (hypothalamus, sensorimotor cortex, and amygdala) in behaviorally passive and active rats with different sensitivity to stress. One-hour immobilization of animals with simultaneous electrocutaneous stimulation was used as a model of stress. An intraperitoneal injection of IL-1β (5 μg/kg) was followed by the decrease in glutathione reductase activity in the hypothalamus of rats. Behaviorally active animals of the IL-1β group were characterized by an increase in the activities of Cu/Zn superoxide dismutase and glutathione peroxidase in the sensorimotor cortex and amygdala, respectively. IL-1β administration was accompanied by activation of Cu/Zn superoxide dismutase and glutathione peroxidase in the amygdala of passive rats. Pretreatment with IL-1β abolished the poststress changes in enzyme activity in the hypothalamus and sensorimotor cortex of active and passive rats, respectively. These data illustrate the specific effects of IL-1β on antioxidant protection of CNS tissues in rats with various behavioral characteristics.

Corticotropin releasing factor-1 receptor antagonism alters the biochemical, but not behavioral effects of repeated interleukin-1β administration

Activation of the immune system via administration of cytokines is used for the treatment of chronic viral infections such as hepatitis C and for cancers resistant to radiotherapy. Cytokine-based treatments induce a range of “sickness” behaviors (e.g. depression, anxiety, pain, anorexia, and fatigue). Activation of the hypothalamic pituitary-adrenal axis via the induction of corticotropin releasing factor (CRF) may underlie these unwanted side effects. This study used repeated systemic injections of the pro-inflammatory cytokine interleukin-1β (IL-1β) to model the sickness behaviors and biochemical effects of immune system activation. We assessed the ability of CRF type I receptor (CRF1) antagonism to reduce biochemical and behavioral signs of sickness induced by IL-1β treatment. Forty Wistar rats were assigned to one of four groups: 1) saline+vehicle; 2) saline+DMP904 (CRF1 antagonist); 3) IL-1β+vehicle; 4) IL-1β+DMP904. Rats received intraperitoneal injections of either DMP904 or vehicle and of IL-1β or saline for six days. Sickness behavior was evaluated using body weight assessments and forced swim testing (FST). Blood and brain samples were collected to measure cytokine, p38 mitogen-activated protein kinase (MAPK), and phospho-p38 MAPK levels using multiplex techniques. There were significant reductions in body weights and FST immobility times associated with IL-1β administration. Rats administered IL-1β had significantly higher serum levels of IL-10, but not interferon-γ. Within the hippocampus, IL-1β reduced levels of p38 MAPK, but had no impact on levels of phospho-p38 MAPK except in the presence of DMP904. When administered alone, DMP904 had no significant effect on p38 MAPK or phospho-p38 MAPK in the hippocampus, but when given with IL-1β led to increased phosphorylation of p38 MAPK. IL-1β and DMP904 reduced levels of p38 MAPK within the hypothalamus, while co-administration of IL-1β and DMP904 abolished the effects of either drug alone. IL-1β decreased immobility time in the FST, and led to reductions in body weight, changes in serum cytokine levels and p38 MAPK regulation within the hippocampus and hypothalamus. DMP904 blocked some of the neurochemical effects of IL-1β, but did not impact the behavioral measures, or serum cytokines. Thus, additional studies will be needed to determine whether CRF1 antagonism is an effective treatment for cytokine-induced sickness.This article is part of a Special Issue entitled ‘Anxiety and Depression’.

Homeostatic alterations after IL-1β microinjection into the nucleus accumbens of the rat

The present study investigates the effects of direct administration of interleukin-1β (IL-1β) into the nucleus accumbens (NAcc) on homeostatic regulation. Short- and long-term food intakes (FI), water intakes (WI) and body temperature (BT) were measured before and after bilateral microinjection of IL-1β (with or without paracetamol pretreatment) into the NAcc of Wistar rats, and the effects were compared with those found in vehicle treated control animals. In addition, blood glucose levels, along with a glucose tolerance test (GTT), and plasma concentrations of metabolic parameters, such as total cholesterol, triglycerides, HDL, LDL and uric acid were determined in cytokine treated and control rats. Short-term FI and WI were suppressed after intraaccumbens application of IL-1β. A significant increase of BT was also observed after the cytokine microinjection. Pretreatment with paracetamol failed to influence the anorexigenic, adipsogenic, and pyrogenic effects of IL-1β. A definite glucose intolerance of the cytokine treated animals and their pathologically elevated blood glucose levels became obvious in the acute GTT. Following IL-1β microinjection, plasma levels of triglycerides, total cholesterol and LDL were found increased. Our present findings show that the NAcc is an important site of action of IL-1β mediated processes in central homeostatic regulation.

Effects of Early Therapeutic Administration of Interleukin-1β on Survival Rate and Bone Marrow Hemopoiesis of Irradiated Mice

The study was aimed at the experimental assessment of the efficacy of recombinant interleukin-1beta in the early therapy of haemopoiesis disorders caused by X-ray irradiation. The efficacy of the product was based on the 30-day survival rate and average life expectancy of dead animals. Endogenous and exogenous colony-formations were studied to reveal possible mechanisms of therapeutic effects of interleukin-1beta on the bone marrow. The early administration (10-15 min after exposure to radiation) of recombinant interleukin-1beta in a dose of 50 microg/kg increased the survival rate and prevented the post-irradiation decrease in the number of endogenous and exogenous CFU-S9 in irradiated mice.

Putting the vasoactive effects of COX-2-derived prostanoids into clinical perspective

Ever since the recognition that the selective inhibitor of cyclooxygenase (COX)-2, rofecoxib, increases the risk for adverse cardiovascular events, enormous attention has been given to the mechanisms underlying these adverse vascular effects of the coxibs.1,2 Many recent studies that have investigated the biological consequences of COX-2 inhibition in the vasculature have focussed either on the prothrombotic side effects of decreased endothelial prostacyclin production during selective COX-2 blockade3,4 or on detrimental effects of such an intervention on atherosclerosis.5,6 Although such studies have greatly broadened our understanding of the pathophysiological roles of COX-2-mediated prostanoid production in vascular biology, the important vasodilatory functions of COX-2-derived prostanoids have been somewhat eclipsed by them. Foudi et al. presents data that address the topic of detrimental vascular effects of COX-2 inhibition from this different, yet important, point of view.7 They show in isolated human internal mammary arteries (IMA) that under conditions of acute septic inflammation, which is induced by simultaneous administration of interleukin-1β (IL-1β) and lipopolysaccharide (LPS), COX-2 is upregulated and produces prostacyclin and prostaglandin E2 (PGE2) rather than thromboxane A2 (TxA2). COX-2 expression is shown to be enhanced not only in the intima, but also in the smooth muscle cell-containing media of the vasculature. When vasoconstriction is induced by norepinephrine in the IMA preparations, COX-2 inhibition leads … Corresponding author. Tel: +49 89 5160 2111; fax: +49 89 5160 2410. E-mail address : florian.kroetz{at}med.uni-muenchen.de