The role of brain cytokines in mediating the behavioral and neuroendocrine effects of intracerebral mycoplasma fermentans.

Intracerebral administration of Mycoplasma fermentans (MF), a small microorganism that has been found in the brain of some AIDS patients, induces behavioral and neuroendocrine alterations in rats. To examine the role of tumor necrosis factor-alpha (TNFalpha) and interleukin-1 (IL-1) in mediating these effects we measured MF-induced expression of TNFalpha and IL-1beta mRNA in various brain regions, and the effects of TNFalpha synthesis blockers and IL-1 receptor antagonist (IL-1ra) on MF-induced sickness behavior and adrenocortical activation. Intracerebroventricular (i.c.v.) administration of heat-inactivated MF induced the expression of both TNFalpha and IL-1beta mRNA in the cortex, dorsal hippocampus, amygdala, and hypothalamus. Pre-treatment of rats with either TNFalpha synthesis blockers, pentoxifylline or rolipram, or with IL-1ra did not attenuate MF-induced anorexia, body weight loss, and suppression of social behavior. However, simultaneous administration of both pentoxifylline and IL-1ra markedly attenuated MF-induced anorexia and body weight loss, but had no effect on the suppression of social behavior. Pre-treatment with pentoxifylline, but not with IL-1ra, significantly attenuated MF-induced corticosterone (CS) secretion. Together, these findings indicate that both TNFalpha and IL-1 participate, in a complementary manner, in mediating some of the behavioral effects of MF, whereas only TNFalpha, but not IL-1, is involved in mediating MF-induced adrenocortical activation. We suggest that cytokines within the brain are involved in mediating at least some of the neurobehavioral and neuroendocrine abnormalities that may be produced by MF in AIDS patients.     

Involvement of brain cytokines in the neurobehavioral disturbances induced by HIV-1 glycoprotein120

Intracerebroventricular (i.c.v.) administration of HIV-1 glycoprotein 120 (gp120), the envelope protein used by the virus to gain access into immune cells, induces neurobehavioral alterations in rats. To examine the role of proinflammatory cytokines in mediating these effects, we measured the effects of gp120 on brain proinflammatory cytokine expression and the effects of anti-inflammatory agents, including interleukin-1 receptor antagonist (IL-1ra), pentoxifylline (a TNFalpha synthesis blocker) and IL-10, on gp120-induced sickness behavior. I.c.v. administration of gp120 induced the expression of IL-1beta, but not TNFalpha, mRNA in the hypothalamus, 3 h after the injection. Pretreatment of rats with IL-1ra, but not with pentoxifylline, significantly attenuated gp120-induced anorexia and loss in body weight, whereas both agents had no effect on gp120-induced reduction in locomotor activity in the open field. Pretreatment with either IL-1ra and pentoxifylline simultaneously, or with IL-10, produced effects that were similar to the effects of IL-1ra alone. Together, these findings indicate that IL-1, but not TNFalpha, mediates some of the behavioral effects of acute gp120 administration, suggesting that brain IL-1 may be involved in some of the neurobehavioral abnormalities evident in AIDS patients.     

Re-exposure to endotoxin induces differential cytokine gene expression in the rat hypothalamus and spleen

This study was designed to investigate whether the pattern of hypothalamic and splenic cytokine expression induced by peripheral administration of a bacterial lipopolysaccharide (LPS) is affected by prior exposure to LPS derived from another bacterial strain. Injection of LPS from Salmonella enteritidis (LPS₂) alone resulted in increased hypothalamic gene expression of IL-1β, IL-6, TNFα, IL-1ra and IL-10. However, pre-exposure to LPS derived from Escherichia coli (LPS₁) 3 weeks before, significantly attenuated hypothalamic IL-1ra, IL-6 and IL-10 expression. IL-1β expression also tended to be lower. This pattern contrasted with the robust cytokine expression in the spleen of LPS₂-treated rats previously exposed to LPS₁, since pre-treatment with endotoxin resulted in a significantly greater response of IL-1β and IL-1ra to LPS₂. Expression of TNFα and IL-10 also tended to be higher. Pre-treatment with LPS₁ did not significantly affect the marked increase in corticosterone and adrenaline blood levels induced by LPS₂. Thus, while endotoxin pre-exposure seemed not to induce a “tolerant” state in the periphery as judged by the immune and endocrine parameters evaluated upon re-stimulation, expression of four of the six cytokines measured was decreased in the hypothalamus. This is the first demonstration that endotoxin priming can differentially affect cytokine expression in the central nervous system and peripheral tissues when a host is confronted with a second, acute, pro-inflammatory stimulus. These results may provide new evidence for the involvement of cytokine pathways in the central nervous system in modulating peripheral inflammation and mediating cognitive and behavioural alterations during inflammatory diseases.     

Effect of Mycoplasma fermentans on brain PGE(2): role of glucocorticoids and their receptors.

OBJECTIVES: Mycoplasmas are a group of eubacteria, which cause various diseases in animals and in humans, and can contribute to diseases produced by other infectious agents, particularly HIV. We have recently reported that intracerebral administration of Mycoplasma fermentans (MF) produces both neuroendocrine and behavioral alterations. Some of these responses were mediated by MF-induced production of prostaglandin E(2 )(PGE(2)). The aim of this study was to examine the role of glucocorticoids (GC) in regulating MF-induced brain prostaglandin production. METHODS: Male rats were injected intracerebroventricularly with various doses of heat-inactivated MF, LPS or IL-1 beta and the following parameters were measured: (1) ex vivo production of hippocampal PGE(2), (2) serum levels of ACTH and corticosterone, and (3) binding capacity of [(3)H]-dexamethasone (DEX) to hippocampal cytosol. RESULTS: MF caused a small increase in hippocampal PGE(2) production, but higher doses failed to produce a further increase. In contrast, the effects of LPS or IL-1 beta on PGE(2) were dose-dependent. Removal of circulating GC by bilateral adrenalectomy significantly enhanced MF-induced brain PGE(2) production. The three immune stimulators increased serum levels of ACTH and corticosterone to the same extent. Finally, MF, but not IL-1 beta increased the specific binding of [(3)H]-DEX to hippocampal cytosol. CONCLUSIONS: Brain PGE(2) induced by MF is regulated by endogenous GC. These hormones have an attenuating effect on PGE(2 )production, probably through an MF-induced increase in GC binding by brain tissue. This mechanism may be important in the pathological effect of MF within the brain of AIDS patients.     

Interleukin-1β-induced brain injury in the neonatal rat can be ameliorated by α-phenyl-n-tert-butyl-nitrone

To examine the possible role of inflammatory cytokines in mediating perinatal brain injury, we investigated effects of intracerebral injection of interleukin-1beta (IL-1β) on brain injury in the neonatal rat and the mechanisms involved. Intracerebral administration of IL-1β (1 μg/kg) resulted in acute brain injury, as indicated by enlargement of ventricles bilaterally, apoptotic death of oligodendrocytes (OLs) and loss of OL immunoreactivity in the neonatal rat brain. IL-1β also induced axonal and neuronal injury in the cerebral cortex as indicated by elevated expression of β-amyloid precursor protein, short beaded axons and dendrites, and loss of tyrosine hydroxylase-positive neurons in the substantia nigra and the ventral tegmental areas. Administration of α-phenyl-n-tert-butyl-nitrone (PBN, 100 mg/kg i.p.) immediately after the IL-1β injection protected the brain from IL-1β-induced injury. Protection of PBN was linked with the attenuated oxidative stress induced by IL-1β, as indicated by decreased elevation of 8-isoprostane content and by the reduced number of 4-hydroxynonenal or malondialdehyde or nitrotyrosine-positive cells following IL-1β exposure. PBN also attenuated IL-1β-stimulated inflammatory responses as indicated by the reduced activation of microglia. The finding that IL-1β induced perinatal brain injury was very similar to that induced by lipopolysaccharide (LPS), as we previously reported and that PBN was capable to attenuate the injury induced by either LPS or IL-1β suggests that IL-1β may play a critical role in mediating brain injury associated with perinatal infection/inflammation.     

Intercellular adhesion molecule-1 expression induced by interleukin (IL)-1β or an IL-1β fragment is blocked by an IL-1 receptor antagonist and a soluble IL-1 receptor

The effects of a recombinant human interleukin-1 (IL-1) receptor antagonist (IL-1ra) and a recombinant human soluble IL-1 receptor (sIL-1R) on cytokine-induced intercellular adhesion molecule-1 (ICAM-1) expression in a human glioblastoma cell line and a neuroblastoma cell line were determined. Cells were incubated with IL-1β, tumor necrosis factor (TNF)α and interferon (IFN)γ. Cells were also tested under identical conditions with an IL-1β synthetic peptide fragment (IL-1β_208–240) previously shown to possess biological activity. IL-1β, TNFα and IFNγ potentiated ICAM-1 expression in both cell lines in a dose-related manner. The IL-1β_208–240 fragments, corresponding to the rabbit, rat and human sequences, enhanced ICAM-1 expression in glioblastoma cells at high doses. ICAM-1 expression induced by IL-1β, rabbit IL-1β_208–240 and human IL-1β_208–240 was blocked by the IL-1ra, while TNFα- and IFNγ-induced ICAM-1 expression were not. ICAM-1 expression induced by IL-1β and human IL-1β_208–240 was also blocked by the sIL-1R. Our findings suggest that IL1β_208–240 acts as an IL-1β agonist in enhancing ICAM-1 expression in vitro and that this effect is receptor-mediated.     

Effects of serotonin synthesis blockade on interleukin-1β action in the brain of rats

The ability of the brain serotonergic system to mediate the effects of interleukin-1β (IL-1β) was investigated. Intracerebroventricular administration of IL-1β induced a significant pyrogenic reaction, depression in social behaviour, loss of body weight and reduced food intake in rats. Pre-treatment with p-chlorphenylalanine, an inhibitor of serotonin synthesis, blocked the IL-1β-induced decrease in food intake and loss of body weight, but failed to alter the temperature increase and the decrease in communicative activity.     

The role of interleukin-1 and tumor necrosis factor α in the neurochemical and neuroendocrine responses to endotoxin

Both interleukin-1 (IL-1) and endotoxin (lipopolysaccharide, LPS) are potent activators of the hypothalamo-pituitary-adrenal (HPA) axis, and they also increase cerebral norepinephrine metabolism and tryptophan. Injections of cause macrophages to synthesize and release various cytokines, including IL-1 and tumor necrosis factor α (TNFα). The hypothesis that macrophage production of IL-1 mediates the HPA-activating effect of LPS was tested in mice using the IL-1-receptor antagonist protein (IRAP). Administration of IRAP largely prevented the effects of IL-1α or IL- 1β on the elevation of plasma corticosterone and the concomitant increase in hypothalamic norepinephrine metabolism, but failed to alter the responses to LPS. IRAP did not prevent the increases in brain tryptophan that occurred after treatment with IL-1 or LPS. Recombinant human TNFa, TNFβ, IL-6, and interferon-a injected intraperitoneally failed to activate the HPA axis, but mouse TNFa was effective by this route, and human TNFα, TNFβ, and IL-6 were effective intravenously. None of these cytokines was as potent as IL-1. Pretreatment with an antibody specific for mouse TNFα, either alone or in combination with IRAP, also failed to prevent the elevation of plasma corticosterone by LPS. Thus, either IL-1 and TNFα are not involved in the HPA and noradrenergic responses to LPS, or there are alternative (redundant) pathways by which LPS can activate the HPA axis.     

Sleep-wake behavior and responses to sleep deprivation of mice lacking both interleukin-1 beta receptor 1 and tumor necrosis factor-alpha receptor 1

Data indicate that interleukin (IL)-1β and tumor necrosis factor-α (TNFα) are involved in the regulation of non-rapid eye movement sleep (NREMS). Previous studies demonstrate that mice lacking the IL-1β type 1 receptor spend less time in NREMS during the light period, whereas mice lacking the p55 (type 1) receptor for TNFα spend less time in NREMS during the dark period. To further investigate roles for IL-1β and TNFα in sleep regulation we phenotyped sleep and responses to sleep deprivation of mice lacking both the IL-1β receptor 1 and TNFα receptor 1 (IL-1R1/TNFR1 KO). Male adult mice (IL-1R1/TNFR1 KO, n = 14; B6129SF2/J, n = 14) were surgically instrumented with EEG electrodes and with a thermistor to measure brain temperature. After recovery and adaptation to the recording apparatus, 48 h of undisturbed baseline recordings were obtained. Mice were then subjected to 6 h sleep deprivation at light onset by gentle handling. IL-1R1/TNFR1 KO mice spent less time in NREMS during the last 6 h of the dark period and less time in rapid eye movement sleep (REMS) during the light period. There were no differences between strains in the diurnal timing of delta power during NREMS. However, there were strain differences in the relative power spectra of the NREMS EEG during both the light period and the dark period. In addition, during the light period relative power in the theta frequency band of the REMS EEG differed between strains. After sleep deprivation, control mice exhibited prolonged increases in NREMS and REMS, whereas the duration of the NREMS increase was shorter and there was no increase in REMS of IL-1R1/TNFR1 KO mice. Delta power during NREMS increased in both strains after sleep deprivation, but the increase in delta power during NREMS of IL-1R1/TNFR1 KO mice was of greater magnitude and of longer duration than that observed in control mice. These results provide additional evidence that the IL-1β and TNFα cytokine systems play a role in sleep regulation and in the alterations in sleep that follow prolonged wakefulness.     

Costimulatory Effects of Interferon-γ and Interleukin-1β or Tumor Necrosis Factor α on the Synthesis of Aβ1-40 and Aβ1-42 by Human Astrocytes

Chronic inflammation and astrocytosis are characteristic histopathological features of Alzheimer's Disease (AD). Astrocytes are one of the predominant cell types in the brain. In AD they are activated and produce inflammatory components such as complement components, acute phase proteins, and cytokines. In this study we analyzed the effect of cytokines on the production of amyloid β (Aβ) in the astrocytoma cell line U373 and in primary human astrocytes isolated postmortem from healthy aged persons as well as from patients with AD. Astrocytes did not produce Aβ in the absence of stimuli or following stimulation with IL-1β, TNFα, IL-6, and TGF-β1. Neither did combinations of TNFα and IL-1β, IL-6 or TGF-β1, or the coadministration of IFNγ and IL-6 or TGF-β1 induce Aβ production. In contrast, pronounced production of Aβ1-40 and Aβ1-42 was observed when primary astrocytes or astrocytoma cells were stimulated with combinations of IFNγ and TNFα or IFNγ and IL-1β. Induction of Aβ production was accompanied by decreased glycosylation of APP as well as by increased secretion of APPsβ. Our results suggest that astrocytes may be an important source of Aβ in the presence of certain combinations of inflammatory cytokines. IFNγ in combination with TNFα or IL-1β seems to trigger Aβ production by supporting β-secretase cleavage of the immature APP molecule.     

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

Activation of peripheral immune cells leads to increases of interleukin-1β (IL-1β) mRNA, immunoreactivity, and protein levels in brain and pituitary. Furthermore, IL-1β 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-1β has received very little attention. A prior report indicated that exposure to inescapable tailshocks (IS) raised levels of brain IL-1β 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-1β protein levels in hypothalamus were elevated by IS in intact subjects, although adrenalectomy, ADX (with basal corticosterone replacement) exaggerated this effect. IL-1β 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-1β protein in the pituitary, and did so in both intact and adrenalectomized subjects. IS also produced increased blood levels of IL-1β, 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-1β in hypothalamus and pituitary, but not in other brain regions or blood.     

TNFα reduces glutamate induced intracellular Ca increase in cultured cortical astrocytes

The proinflammatory cytokine TNFα is locally released during various inflammatory CNS diseases and high cerebrospinal fluid (CSF) titers of TNFα were found in meningitis patients. We know from previous studies that TNFα also depolarizes astrocytes by reducing their inwardly rectifying K⁺ currents. We have now investigated the effect of TNFα on the glutamate induced intracellular Ca²⁺ increase in astrocytes, a process which seems to be involved in glial mediated modulation of neuronal synaptic transmisssion. Incubation with TNFα (50–1000 U/ml for 60 min) reduces the glutamate induced intracellular Ca²⁺ increase in astrocytes but not in neurons and this seems to be a phenomenon secondary to the TNFα induced depolarization. While other proinflammatory cytokines (interleukin 1β, IL-2, IL-6) did not interfere with the astrocytic glutamate response, incubation in CSF from septic meningitis patients (CSF–SM) also reduced the glutamate induced intracellular Ca²⁺ increase. The application of a neutralizing anti-TNFα antibody to the CSF–SM prior to cell incubation partially restored the glutamate response. Our data suggest that inflammatory molecules such as TNFα impair astrocytes’ response to glutamate and this may indirectly affect neuronal synaptic transmission.     

Differential effects of IL-1ra on sickness behavior and weight loss induced by IL-1 in rats

Peripheral and central injections of recombinant human interleukin-1β (IL-1β) have been shown to decrease social exploration and to induce body weight loss in rats. To characterize the receptor mechanisms of these effects, we used as a tool a specific antagonist of the receptors of IL-1, IL-1ra. Intraperitoneal (i.p.) administration of IL-1ra (8 mg/kg) blocked the effect of i.p. injection of IL-1β (4 μg/rat) on social behaviour but not on body weight. Central administration of IL-1ra (60 μg/rat, i.c.v.) abrogated the effects of centrally administered IL-1β (30 ngn/rat, i.c.v.) on both social behaviour and body weight. Central injection of IL-1ra (4 μg/rat, i.c.v.) also attenuated the effects of i.p. administered IL-1β (4 μg/rat) on social behaviour but not on body weight. These results suggest that the effects of IL-1β on social behavior are mediated centrally and that its effect on the loss of body weight involves different receptor mechanisms.     

Tumor necrosis factor-α attenuates N-methyl-d-aspartate-mediated neurotoxicity in neonatal rat hippocampus

Tumor necrosis factor-α (TNFα) has been implicated in the pathophysiology of acute neonatal brain injury. We hypothesized that acute brain injury would induce TNFα expression and that exogenous TNFα would influence the severity of N-methyl-d-aspartate-induced tissue damage. We performed two complementary groups of experiments to evaluate the potential role(s) of TNFα in a neonatal rodent model of excitotoxic injury, elicited by intracerebral injection of N-methyl-d-aspartate. We used immunohistochemistry and ELISA to evaluate N-methyl-d-aspartate-induced changes in TNFα expression, and we co-injected TNFα with N-methyl-d-aspartate, to evaluate the effect of this cytokine on the severity of tissue injury. Both intra-hippocampal and intra-striatal injection of N-methyl-d-aspartate (5 nmol) stimulated TNFα expression. Increased TNFα expression was detected 3–12 h after lesioning; TNFα was localized both in glial cells in the corpus callosum, and in cells with the morphology of interneurons in the ipsilateral hippocampus, striatum, cortex and thalamus. Intra-hippocampal or intra-striatal administration of TNFα (50 ng) alone did not elicit neuropathologic damage. In the hippocampus, when co-injected with N-methyl-d-aspartate (5 or 10 nmol), TNFα (50 ng) attenuated excitotoxic injury by 35%–57%, compared to controls co-injected with heat-treated TNFα. In contrast, in the striatum, co-injection of TNFα with N-methyl-d-aspartate had no effect on the severity of the ensuing damage. The data indicate that TNFα is rapidly produced in glial cells and neurons after an excitotoxic insult in the neonatal rat brain, and that administration of exogenous TNFα results in region-specific attenuation of excitotoxic damage. We speculate that endogenous TNFα may modulate the tissue response to excitotoxic injury in the developing brain.     

Intracerebral interleukin-1β impairs response to tumor invasion: involvement of adrenal catecholamines

Interleukin-1β (IL-1β) is released within the brain following stress, trauma, infection, and in specific brain disorders. This centrally acting IL-1β has recently been shown to impair peripheral immunity. Central administration of IL-1β suppresses natural killer (NK) cell activity impairs lung clearance of tumor cells and enhances tumor colonization. Using an in vivo model of tumor colonization (lung clearance of NK-sensitive MADB106 adenocarcinoma cells), this study examined the role of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) in mediating these effects. We demonstrate that adrenalectomy significantly attenuated the impaired lung clearance of MADB106 tumor cells induced by intracerebroventricular (i.c.v.) administration of IL-1β (20 ng). Supplementing adrenalectomized animals with corticosterone did not reinstate the effect. The effect of IL-1β on lung clearance was blocked by pretreatment with the β-adrenergic antagonist, nadolol (0.5 mg/kg), but not by the α-antagonist phentolamine (5 mg/kg). Peripheral noradrenergic pathways are not implicated given that systemic administration of the noradrenergic neurotoxin, 6-hydroxydopamine, did not block the effect of IL-1β. Taken together, these findings indicate that IL-1β impairs lung clearance of MADB106 tumor cells via the actions of adrenal catecholamines, most likely epinephrine, acting at β-adrenergic receptors in the periphery.     

Dual effects of interleukin-1β on N-methyl- -aspartate-induced retinal neuronal death in rat eyes

In this study we determine if interleukin-1β (IL-1β) modulates N-methyl- -aspartate (NMDA)-induced retinal damage. Sprague–Dawley rats were anesthetized with inhalation of halothane, after which a single injection of 5 μl of IL-1β (0.1 to 10 ng/eye) (and/or IL-1 receptor antagonist (IL-1ra)) for experimental eyes was administered. Two days later (or simultaneously), NMDA (20 nmol) was injected into the vitreous space. One week later, each eye was enucleated and transverse sections were subjected to morphometric analysis. Enzyme-linked immunosorbent assay (ELISA) was conducted for the determination of IL-1β levels in retina. Immunohistochemical and immunoblot studies were also performed. In eyes that received an intravitreal injection of IL-1β (0.1 to 10 ng/eye), significant thinning of the inner plexiform layer (IPL) was observed (P<0.05). Immunohistochemical and ELISA studies demonstrated upregulated expression of IL-1β in retinas that had undergone NMDA injection. Treatment with 10 ng of IL-1ra induced a protective effect against NMDA-induced retinal damage. Pretreatment with IL-1β induced a significant protective effect on NMDA-induced retinal damage. Our studies suggest that IL-1β induces neuronal cell death directly, as shown by the protective effects of IL-1ra, but has a protective effect on NMDA-induced retinal damage indirectly after an incubation time of at least 2 days.     

Interferon β-1a downregulates TNFα-induced intercellular adhesion molecule 1 expression on brain microvascular endothelial cells through a tyrosine kinase-dependent pathway

TNFα (100 U/ml, 24 h) upregulated intercellular adhesion molecule 1 (ICAM1) expression on brain microvascular endothelial cell (BMEC) culture. The tyrosine kinase (TK) inhibitor genestein (100 μg/ml), the protein kinase C (PKC) inhibitor staurosporin (1 nM), and interferon (IF) β-1a (1000 U/ml) antagonized TNFα effect. When an ineffective dose of IFβ-1a (100 U/ml) was challenged with ineffective doses of either genestein (10 μg/ml) or staurosporin (0.1 nM), the combination IFβ-1a–genestein significantly reduced TNFα-induced ICAM1 expression whereas IFβ-1a–staurosporin did not. These findings indicate that a TK- rather than a PKC-dependent mechanism is involved in the modulation of TNFα response by IFβ-1a on BMECs.     

Chelerythrine, a selective protein kinase C inhibitor, counteracts pyrogen-induced expression of tissue factor without effect on thrombomodulin down-regulation in endothelial cells

Endotoxin, interleukin1 β (IL-1β) and tumor necrosis factorα (TNF-α) dose-dependently increased the expression of tissue factor and at the same time induced thrombomodulin down-regulation on the surface of cultured bovine aortic endothelial cells. Chelerythrine, a selective protein kinase C inhibitor, strongly reduced endotoxin-, IL1β- and TNFα-induced tissue factor expression but remained without effect with regard to thrombomodulin down-regulation measured in parallel. On the contrary, staurosporine, a highly potent, non-selective PKC inhibitor, simultaneously abolished tissue factor expression and thrombomodulin down-regulation induced by endotoxin, IL1β and TNFα. These results show that protein kinase C is deeply involved in the process leading to pyrogen-induced tissue factor expression and suggest that thrombomodulin down-regulation is regulated by a different pathway.     

Murine tumor necrosis factor alpha is transported from blood to brain in the mouse

The cytokines are important components of the brain-immune axis. Recent work has shown thet [¹²⁵I]IL-1α and [¹²⁵I]IL-1β are transported from the blood into the brain by a saturable system. Here we show that murine tumor necrosis factor alpha (mTNFα)_ labeled with ¹²⁵I (I-mTNFα) crosses the blood-brain barrier (BBB) after i.v. injection by a transport system different from that for the interleukins. Self inhibition with mTNFα showed that this transport system was saturable, and lack of inhibition by IL-1β, IL-6, or MIP-1α showed selectivity of the system. High performance liquid chromatography (HPLC) of the radioactivity recovered from brain and from cerebrospinal fluid after the i.v. injection of I-mTNFα showed that the cytokine crossed the BBB largely in intact form. Capillary depletion showed that the accumulation of I-mTNFα in the cerebral cortex was due to passage across the BBB rather than to sequestration by capillaries. Transport rate was not changed by acute treatment with the neurotoxin aluminium or by acute and chronic treatment with the cationic chelator deferoxamine, but it was more than three times faster in neonatal rats. Efflux of I-mTNFα from the brain was slower than would have been predicted based on reabsorption of cerebrospinal fluid, suggesting that TNFα is sequestered by the brain. The BBB was not disrupted by up to 50 μg kg⁻¹ of mTNFα i.v. in either adult mice or neonatal rats as assessed by the BBB's impermeability to radioactively labeled albumin. The saturable transport of mTNFα across the BBB supports the concept of direct blood to brain transport of cytokines as a mechanism by which the peripheral immune system can affect brain function.     

Human immunodeficiency virus-1 coat protein gp120 impairs contextual fear conditioning: a potential role in AIDS related learning and memory impairments

Many AIDS patients suffer from cognitive impairments including deficits in learning and memory. The Human Immunodeficiency Virus-1 (HIV-1) envelope glycoprotein gp120 is one possible mediator of these impairments. This is because gp120 activates brain microglial cells and astrocytes, and in vivo activation of glia leads to the release of the proinflammatory cytokine interleukin-1 beta (IL-1β). gp120 induced IL-1β release could be involved in producing memory impairments associated with AIDS because central IL-1β activity adversely affects cognitive function. The reported experiments evaluated the effects of i.c.v. gp120 administration and subsequent IL-1β activity on learning and memory processes in the rat. Intracerebroventricular gp120 produced memory impairments on hippocampally dependent contextual fear conditioning, but not hippocampally independent auditory-cue fear conditioning following post-conditioning gp120 administration. Central gp120 administration also caused increases in IL-1β protein levels in the hippocampus and frontal cortex but not in the hypothalamus. gp120 induced memory impairments were blocked by 2 different IL-1 antagonists, alpha melanocyte stimulating hormone (αMSH) and interleukin-1 receptor antagonist (IL-1ra). Finally, heat denaturation of the tertiary structure of gp120 abolished its effects on fear conditioning, suggesting that gp120 impairs contextual fear conditioning by binding to its receptors on glia.