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The Journal of Neuroscience, July 2, 2003, 23(13):5536-5544
Previous Article | Next Article
Glucocorticoids Play a Fundamental Role in Protecting the Brain during Innate Immune Response
Sylvain Nadeau andSerge Rivest Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center and Department of Anatomy and Physiology, Laval University, Québec, Canada G1V 4G2
Abstract
Top
Abstract
Introduction
The innate immune system plays a crucial role in protecting the host against infectious microorganisms. An inappropriate control of this system may have profound consequences, because of the maintained production of specific proinflammatory molecules. Glucocorticoids are the most efficient endogenous molecules that provide negative feedback on proinflammatory signaling and gene expression. Here we show that activation of this system is not detrimental for the brain but a profound neurodegeneration takes place in animals treated with the glucocorticoid receptor inhibitor Mifepristone (RU486). This drug increased the inflammatory reaction induced by a single intracerebral bolus of lipopolysaccharide (LPS). Inhibition of tumor necrosis factor(TNF-
Key words: caspases; cytokines; gram-negative cell wall component; inflammation; innate immunity; microglia; neurodegeneration; NF-
B; TNF-
Introduction
Glucocorticoids (GCs) are involved in the regulation of many physiological systems, but inappropriate regulation of this endocrine axis has profound consequences for the organism. One known outcome of elevated GC levels in stressed individuals is exacerbation of the rate of neuronal cell death during normal aging (Sapolsky, 1996). On the other hand, GCs are the most powerful endogenous immunosuppressors, especially for the innate immune response and the subsequent inflammatory reaction (McKay and Cidlowski, 1999
Such fine control of GCs on the innate immune system and the inflammatory reaction may also exist in the CNS. For a long time, the brain was considered to be a privileged organ from an immunological point of view, because of its inability to mount an immune response and process antigens. Although this is partly true, the CNS shows a well organized innate immune reaction in response to systemic bacterial infection and cerebral injuries (for review, see Nguyen et al., 2002
It is possible that endogenous GCs play a crucial role in the fate of the immune system in the brain. Therefore, this study tested the hypothesis that GCs are essential modulators of the innate immune system in the CNS, and alteration of this negative feedback may be associated with cerebral damage.
Materials and Methods
Animals. Adult male Sprague Dawley rats (Charles River Canada, St. Constant, Quebec, Canada;200 gm) were acclimated to standard laboratory conditions (14 hr light/10 hr dark cycle; lights on at 6 A.M. and off at 8 P.M.) with ad libitum access to rat chow and water. Animal breeding and experiments were conducted according to Canadian Council on Animal Care guidelines, as administered by the Laval University Animal Care Committee. A total of 168 rats were assigned to four different protocols divided among the treatment and route of administration.
Surgeries and treatments. Animals were anesthetized with an intraperitoneal injection of a mixture (1 ml/kg body weight) of ketamine hydrochloride (91 mg/kg) and xylazine (9 mg/kg), and the site of injection was reached stereotaxically (David Kopf Instruments, Tujunga, Ca). With the incisor bar placed at 3.3 mm below the interaural line (horizontal zero), the coordinates from bregma for the guide cannula (22 gauge; C313G, Plastic One, Roanoke, VA) were –0.6 mm anteroposterior, –3.3 mm lateral, and –2.8 mm dorsoventral. The guide cannula was secured with screws and cranioplastic cement (cranioplastic powder, Plastic One; Dentsply repair material, Dentsply International, York, PA). The rats were then housed individually for a 10 d recuperation period. During the first 3 d after the surgery, rats received once daily a subcutaneous injection of 8 ml of Ringer's lactate (Abbott Laboratories, Saint-Laurent, Canada) and 150 µl ketoprofen (Rhône Mérieux Canada, Victoriaville, Canada).
On the day of the first set of experiments (
A second protocol was performed to determine the respective contribution of tumor necrosis factor
(IL-1
The third series of experiments verified the effects of a chronic infusion of recombinant rat (rr)TNF-
A fourth set of experiments was performed to investigate the mechanisms mediating the cytotoxic effects of TNF-
Brain preparation and in situ hybridization histochemistry. Animals were deeply anesthetized after the different treatments with an intraperitoneal injection (500 µl) of a mixture of ketamine hydrochloride and xylazine and then rapidly perfused transcardially with 0.9% saline, followed by 4% paraformaldehyde in 0.1 M sodium phosphate buffer, pH 7.4, at 4°C. Brains were removed from the skull, postfixed for 2 hr, and then placed in 20% sucrose diluted in 4% paraformaldehyde-sodium phosphate buffer for 12–15 hr. The brains were mounted on a microtome (Reichert-Jung, Cambridge Instruments Company, Deerfield, IL), frozen with dry ice, and cut into 30 µm coronal sections from the olfactory bulb to the end of the medulla. The slices were collected in a cold cryoprotectant solution (0.05 M sodium phosphate buffer, pH 7.3, 30% ethylene glycol, 20% glycerol) and stored at –20°C.
The riboprobes used in this study are described in Table 1; in situ hybridization using 35S-labeled cRNA probes was accomplished as described previously (Laflamme et al., 1999
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Table 1. Plasmids and enzymes used for probe synthesis
Detection of demyelination, cell death, and apoptosis. Demyelination was determined via Luxol Fast Blue (LFB) staining. Every sixth section of the whole rostrocaudal extent of each brain was mounted onto poly-L-lysine-coated slides, dried overnight under vacuum, dehydrated through graded concentrations of alcohol (50, 70, and 95%, 1 min each), and incubated at 60°C for 6 hr in LFB solution [Solvent Blue 38 1% (Sigma) in 95% ethanol and 0.5% acetic acid]. The sections were then rinsed in 95% alcohol (1 min), 0.05% lithium carbonate (Sigma; 1–5 min), and 70% alcohol (two dips). Thereafter, the slides were incubated in 1% eosine Y solution (EM Diagnostic Systems, Gibbstown, NJ) for 40 sec, rinsed in distillated water, incubated in 0.25% cresyl violet (Sigma) for 40 sec, rinsed in distillated water, dehydrated through graded concentrations of alcohol (50, 70, 95, and 100%; 1 min each), cleared in xylene for 1 min (two times), and coverslipped with distrene plasticizer xylene (DPX) (Electron Microscopy Sciences, Fort Washington, PA).
Apoptotic cells were labeled by immunohistochemistry using a cleaved caspase-3 monoclonal antibody. Brain sections were washed in sterile DEPC-treated 50 mM potassium PBS (KPBS) and incubated 48 hr at 4°C with the cleaved caspase-3 antibody Asp 175 (Cell Signaling Technology, Mississauga, Ontario, Canada), which was diluted in sterile KPBS (1:500) + 0.4% Triton X-100 + 1% BSA (fraction V, Sigma). After incubation with the primary antibody, brain slices were rinsed in sterile KPBS and incubated with a mixture of KPBS + 0.02% Triton X-100 + 1% BSA + Cy2-conjugated anti-rabbit IgG antibody (1:1500; Jackson ImmunoResearch Laboratory, West Grove, PA) for 3 hr in a dark room at 20°C. Tissues were thereafter rinsed in sterile KPBS, mounted onto poly-L-lysine slides, and coverslipped with a polyvinyl alcohol (Sigma) mounting medium containing 2.5% 1,4-diazabicyclo(2,2,2)-octane (Sigma) in buffered glycerol (Sigma).
Cell death by apoptosis was also detected via a TdT-FragEL DNA Fragmentation Detection Kit (Oncogene Research Products, San Diego, CA). Positive controls were generated from brain sections of animals that received only sham treatments. These sections were mounted on the slides and covered with 1 µg/µl DNase I in 1x TBS/1 mM MgSO4 for 20 min at room temperature.
Neuronal death was labeled with the Fluoro-Jade B (FJB) method. Briefly, every sixth section of the whole rostrocaudal extent of each brain was mounted onto poly-L-lysine-coated slides, dried under vacuum for 2 hr, dehydrated through graded concentrations of alcohol (50, 70, and 100%, 1 min), and rehydrated through graded concentrations of alcohol (100, 70, and 50%, 1 min each) and 1 min in distillated water. They were then dipped into and shaken in potassium permanganate (0.06%) for 10 min, rinsed 1 min in distillated water, and dipped into and shaken in a solution containing Fluoro–Jade B [Fluoro–Jade B 0.0004% (Histochem, Jefferson, AR) + acetic acid 0.1% (Sigma) + DAPI 0.0002% (Molecular Probes Eugene, OR)] for 20 min. The slides were thereafter rinsed three times in distillated water (1 min each), dried, dipped in xylene three times (2 min each), and coverslipped with DPX.
Nissl stain was also used as a general index of cellular morphology that may be altered in response to the different treatments.
Staining of infiltrating cells. The Wright stain was used to visualize infiltrating cells within brain parenchyma, and their identification was based on the morphology and color of cytoplasm, nucleus, and granulations. Every sixth section of the whole rostrocaudal extent of each brain was mounted onto poly-L-lysine-coated slides, dried under vacuum for 1 hr, and covered with 2 ml of Wright staining solution (Bayer Corporation Diagnostics Division, Elkhart, IN) for 90 sec. They were then covered with an additional 2 ml of buffer solution for 3 min and washed with the rinse solution provided by the company. Sections were immediately dipped in Xylene and coverslipped with DPX-mounting medium.
Quantitative analysis. Hybridization signals were quantified on x-ray films (Biomax). Briefly, transmittance values (optical density) of the hybridization signal were measured under a Northern Light Desktop Illuminator (Imaging Research) using a Sony Camera Video System attached to a Micro-Nikkor 55 mm-Vivitar extension tube set coupled to a computer and NIH Image software version 1.59/ppc [written by W. Rasband (National Institutes of Health) and available from the internet by anonymous ftp from http://rsb.info.nih.gov/nih-image/download.html]. Optical density (O.D.) values for each pixel were calculated using a known standard of intensity and distance measurements from a logarithmic specter adapted from Bioimage Visage 110s (Millipore, Ann Arbor, MI). The entire hemisphere ipsilateral to the injection site was digitized and subjected to densitometric analysis, yielding measurements of mean density per area. The O.D. of each hemisphere was then corrected for the average background signal by subtracting the O.D. of area without positive signal located in the contralateral side. All measurements were performed in triplicate. Data were reported as mean O.D. values (± SEM).
Demyelination was evaluated on LFB-stained sections that were digitized with an RT-SPOT camera (Diagnostic Instruments, Sterling Heights, MI) mounted directly onto a microscope (BX-60, Olympus) and connected to a computer (PowerMac G4, Macintosh, Apple Computer). The O.D. of corpus callosum and caudoputamen was measured using the NIH Image software, and values of the contralateral side were subtracted from those of the ipsilateral side of three different rostrocaudal levels.
The necrotic area was measured with the NIH Image software, and the data are reported as arbitrary units, whereas the number of FJB- and cleaved caspase-3-positive cells was calculated manually. An area of 250 x 250 mm2 was drawn on the computer monitor, and the number of positive cells was counted manually and reported as the mean number of positive cells per mm2 (±SEM).
The statistical analyses for the different dependent variables were performed by a two-way ANOVA followed by a Bonferroni/Dunn test procedure as post hoc comparison. Please see the figure legends for more specific details.
Results
Innate immune response in the site of injection
A single intrastriatal infusion of LPS caused profound transcriptional activation of numerous genes involved in the control of the innate immune response. Representative examples of such phenomena are depicted in Figure 1. There was no positive signal in the CNS of rats that received an intraperitoneal injection with either the vehicle solution (DMSO) or RU486 before the intrastriatal infusion of saline. However, TNF-
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Figure 1. Time-related induction of genes encoding proinflammatory proteins and caspase-8 in the brain of rats that received a single bolus of lipopolysaccharide (LPS) in the dorsal striatum. Animals received a systemic injection with vehicle (DMSO) or the glucocorticoid receptor inhibitor RU486 12 hr before the intraparenchymal challenge with the endotoxin. The dark-field photomicrographs were taken from brain coronal sections hybridized with different radioactive riboprobes and dipped into nuclear emulsion milk (Kodak). The pictures of the first row depict representative examples of the expression pattern of the inhibitory factor p<0.05 from their corresponding RU486/vehicle and DMSO/LPS groups. Magnification, 3.125 x. Scale bar, 1000 µm.
Inhibition of GCRs changed the inflammatory reaction provoked by the single LPS bolus. At time 12 hr after intrastriatal LPS infusion, the proinflammatory genes were strongly induced in the brain of rats pretreated or not with RU486, and the signal intensity was similar between both groups of animals. However, expression levels of the immune transcripts were significantly higher in the brain of rats that received RU486 before the intraparenchymal bolus of LPS and killed 3 d later. The hybridization signals for CD14 and I
Effect of RU486 on cerebral integrity
The data that RU486 is able to exacerbate the innate immune response in the brain were expected, because GCs act as the critical endogenous negative feedback for the proinflammatory signal transduction pathways and gene transcription. Without such feedback, a single LPS bolus became highly toxic for the cerebral tissue (Fig. 2). Despite the strong and transient inflammatory reaction in regions ipsilateral to the site of infusion, the endotoxin did not affect the cerebral tissue that was evaluated via numerous approaches. In contrast, LPS provoked a nonspecific cell death in animals pretreated with RU486. A localized wound was observed at the site of infusion 36 hr after the treatment combining RU486 with LPS, but the extent of the tissue damage was variable among animals. The fluorochrome FJB, a sensitive and reliable marker for the histochemical localization of neuronal degeneration, was already apparent 36 hr after the insult. The magnitude and intensity of FJB signal increased dramatically 3 d after LPS administration in rats pretreated with the drug inhibiting GCRs. This was also the case for apoptotic cells that were labeled via a TdT-FragEL DNA fragmentation detection kit and by immunohistochemistry using an antibody directed against anti-cleaved caspase-3 (Table 2, Fig. 2C,D). Cleaved caspase-3-immunoreactive signal was already robust in neurons ipsilateral to the site of LPS infusion at time 36 hr after LPS and RU486 treatment (Fig. 2 D). The progressive change in neuronal integrity was accompanied by an influx of infiltrating cells, mainly neutrophils, lymphocytes, and monocytes (Fig. 2 E).
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Figure 2. A single intraparenchymal lipopolysaccharide (LPS) injection causes a major neurodegeneration in rats pretreated with RU486. Animals received an intraperitoneal injection of either vehicle solution (DMSO) or RU486 (50 mg/kg) 12 hr before the intracerebral infusion of either vehicle solution (saline) or LPS (5 µg/2 µl for 2 min). A, Panels depict representative examples of demyelination and necrotic tissues stained with Luxol Fast Blue. B, Panels show examples of Fluoro-Jade B staining used here as index of neurodegeneration. Apoptotic cells are depicted by the images in the panels in C (DNA fragmentation) and D (immunoreactive cleaved caspase-3 cells). The nonspecific staining is caused by the primary antisera, because no signal was found in tissues (from both control and treated rats) incubated without primary antibody. This staining is unlikely to reveal cleaved caspase-3 in control brains, because this enzyme and its substrates are not located in the nucleus but in the cytoplasm, as depicted by the apoptotic cells of the two right panels in D. E, Panels show the progressive destruction of the extracellular matrix, modification of the neuronal morphology, and appearance of infiltrating cells detected by means of the LFB staining. All photomicrographs were taken at the same rostrocaudal level. Black arrows indicate infiltrating cells; white arrows indicate neurons. Magnification: A, B, 3.125x; C–E, 100x. Scale bars: A, B, 1000 µm; C–E, 100 µm.
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Table 2. Quantification of brain damage caused by the intraparenchymal LPS infusion in rats pretreated with the glucocorticoid receptor inhibitor RU486
It is interesting to note that the striatum seems more resistant than the cortex to LPS in RU486-treated rats, but this phenomenon was quite variable among animals, the injection site, and the rostrocaudal level. It is nevertheless possible that the backflow of the injected solution explains the more localized damage in the cortex.
Role of cytokines in mediating LPS-induced neurotoxicity
These results provide solid anatomical evidence that the release of GCs is a critical mechanism in protecting the cerebral tissue when infused with a cell wall component derived from gram-negative bacteria. The genes encoding TNF-
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Figure 3. Role of interleukin 1 p<0.05 from the anti-IL-1
Mechanisms involved in the effects of TNF-
To this point, our data indicate that IL-1
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Figure 4. Chronic infusion of tumor necrosis factor
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Table 3. Quantification of brain damage induced by chronic injection of either vehicle solution (Veh) or TNF-
To investigate the mechanisms involved in the cytotoxic effects of TNF-
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Figure 5. Partial role of nitric oxide (NO) and caspase pathways in the neurotoxic effects of TNF-
Discussion
The present set of data provides solid evidence that GCs play a critical role in the control of the innate immune system in the brain. Without such control, activation of this system has profound consequences for the cerebral elements and provokes irreversible damage. A single intraparenchymal bolus of LPS was able to increase the transcription of various genes involved in the innate immune response, and such a phenomenon did not alter the neuronal integrity, which was verified via a number of approaches. Cell death induced by apoptosis was never observed in the brain of LPS-treated animals. Other histological straining procedures also failed to provide anatomical evidence that LPS and its induced inflammatory reaction have detrimental effects. Cell bodies, dendrites, and fibers were not changed in regions depicting the robust expression wave of immune genes, including the basal ganglia, hippocampal formation, cerebral cortex, and fibers of the corpus callosum. Finally, the marker of neuronal degeneration, FJB, remained undetectable in the brain of LPS-challenged animals.This immune reaction, however, surprisingly became highly toxic for the cerebral tissue in rats pretreated with the GCR inhibitor RU486. The ability of GCs to modulate the innate immune response in the brain was expected, because these hormones are the most potent negative regulators of the proinflammatory signal transduction pathways and gene expression in macrophages and other systemic antigen-presenting cells (Webster et al., 2002
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Figure 6. Neuroprotective action of glucocorticoids (GCs) during innate immune response. A single intracerebral bolus of lipopolysaccharide (LPS) causes a strong and transient production of proinflammatory cytokines by microglial cells. Tumor necrosis factor
Of interest is the nonspecific tissue destruction by the single LPS bolus in rats that received the GCR inhibitor. The same phenomenon took place in the brain after the chronic administration of TNF, but the cytokine took longer than LPS to damage the brain. Indeed, although the wound was already present 36 hr after the combined treatment of LPS and RU486 and this effect was abolished by inhibiting the biological activity of the cytokine, the first signs of degeneration were found only between 3 and 7 d of chronic TNF infusion. It is possible that the concentration selected to deliver the cytokine chronically does not reflect the levels reached in the extracellular milieu when the endotoxin was injected in GC-deficient rats. The concentrations of TNF are actually determinant for the shift between cell survival and cell death (Sugarman et al., 1985
Other cytokines may explain the delay between the treatment of LPS with RU486 and chronic TNF-
The dichotomy of activated astrocytes and microglia as impediments or facilitators of CNS recovery is a common concept in the fields of regeneration and inflammation research. Studies havepointed out that the beneficial or noxious effects of astrogliosis and microgliosis are dependent on the duration of activation of glial cells (Streit et al., 1999
The binding of TNF-
Other mechanisms are nevertheless involved, because caspase inhibition did not completely abolish the neurotoxic effects of TNF-
In summary, the inflammatory response lasted longer in the brain of animals that received the GR antagonist RU486 before the intracerebral LPS infusion. Surprisingly, a single bolus of LPS caused a rapid and severe neurodegeneration in RU486-pretreated animals. This neurotoxic effect of LPS was essentially abolished by inhibiting the biological activity of TNF-
Footnotes
Received Feb. 4, 2003; revised Apr. 9, 2003; accepted Apr. 21, 2003.This research was supported by the Canadian Institutes of Health Research (CIHR). Sylvain Nadeau holds a Studentship from the CIHR and Serge Rivest is a CIHR Scientist and holds a Canadian Research Chair in Neuroimmunology. We thank Dr. A. Israel (Institut Pasteur, Paris, France) for the mouse I
Correspondence should be addressed to Dr. Serge Rivest, Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center, 2705 Boulevard Laurier, Québec, Canada, G1V 4G2. E-mail: Serge.Rivest{at}crchul.ulaval.ca.
Copyright © 2003 Society for Neuroscience 0270-6474/03/235536-09$15.00/0
References
Allan SM, Rothwell NJ (2001) Cytokines and acute neurodegeneration. Nat Rev Neurosci 2: 734–744.[Web of Science][Medline]
Beg AA, Baltimore D (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274: 782–784.
[Abstract/Free Full Text] Chan FK, Siegel RM, Lenardo MJ (2000) Signaling by the TNF receptor superfamily and T cell homeostasis. Immunity 13: 419–422.[Web of Science][Medline]
De Bosscher K, Schmitz ML, Vanden Berghe W, Plaisance S, Fiers W, Haegeman G (1997) Glucocorticoid-mediated repression of nuclear factor-kappaB-dependent transcription involves direct interference with transactivation. Proc Natl Acad Sci USA 94: 13504–13509.
[Abstract/Free Full Text] Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell [Suppl] 109: S81–96.
Herx LM, Rivest S, Yong VW (2000) Central nervous system-initiated inflammation and neurotrophism in trauma: IL-1beta is required for the production of ciliary neurotrophic factor. J Immunol 165: 2232–2239.
[Abstract/Free Full Text] Karin M, Lin A (2002) NF-kappaB at the crossroads of life and death. Nat Immunol 3: 221–227.[Web of Science][Medline]
Kawai T, Adachi O, Ogawa T, Takeda K, Akira S (1999) Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11: 115–122.[Web of Science][Medline]
Laflamme N, Rivest S (1999) Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor kappa B alpha within specific cellular populations of the rat brain. J Neurochem 73: 309–321.[Web of Science][Medline]
Laflamme N, Rivest S (2001) Toll-like receptor 4: the missing link of the cerebral innate immune response triggered by circulating gram-negative bacterial cell wall components. FASEB J 15: 155–163.
[Abstract/Free Full Text] Laflamme N, Lacroix S, Rivest S (1999) An essential role of interleukin-1
[Abstract/Free Full Text] Laflamme N, Souci G, Rivest S (2001) Circulating cell wall components derived from gram-negative and not gram-positive bacteria cause a profound transcriptional activation of the gene encoding toll-like receptor 2 in the CNS. J Neurochem 70: 648–657.
McKay LI, Cidlowski JA (1999) Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev 20: 435–459.
[Abstract/Free Full Text] Nadeau S, Rivest S (2000) Role of microglial-derived tumor necrosis factor in mediating CD14 transcription and NF-
[Abstract/Free Full Text] Nadeau S, Rivest S (2001) The complement system is an integrated part of the natural innate immune response in the brain. FASEB J 15: 1410–1412.
[Abstract/Free Full Text] Nadeau S, Rivest S (2002) Endotoxemia prevents the cerebral inflammatory wave induced by intraparenchymal lipopolysaccharide injection: role of glucocorticoids and CD14. J Immunol 169: 3370–3381.
[Abstract/Free Full Text] Nguyen MD, Julien JP, Rivest S (2001) Induction of proinflammatory molecules in mice with amyotrophic lateral sclerosis: no requirement for proapoptotic interleukin-1beta in neurodegeneration. Ann Neurol 50: 630–639.[Web of Science][Medline]
Nguyen MD, Julien JP, Rivest S (2002) Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 3: 216–227.[Web of Science][Medline]
Rothwell NJ, Luheshi GN (2000) Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci 23: 618–625.[Web of Science][Medline]
Sapolsky RM (1996) Why stress is bad for your brain. Science 273: 749–750.[Web of Science][Medline]
Siegel RM, Lenardo MJ (2001) To B or not to B: TNF family signaling in lymphocytes. Nat Immunol 2: 577–578.[Medline]
Streit WJ, Walter SA, Pennell NA (1999) Reactive microgliosis. Prog Neurobiol 57: 563–581.[Web of Science][Medline]
Sugarman BJ, Aggarwal BB, Hass PE, Figari IS, Palladino MA Jr, Shepard HM (1985) Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science 230: 943–945.
[Abstract/Free Full Text] Thibeault I, Laflamme N, Rivest S (2001) Regulation of the gene encoding the monocyte chemoattractant protein 1 (MCP-1) in the mouse and rat brain in response to circulating LPS and proinflammatory cytokines. J Comp Neurol 434: 461–477.[Web of Science][Medline]
Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM (1996) Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 274: 787–789.
[Abstract/Free Full Text] Wang CY, Mayo MW, Baldwin AS Jr (1996) TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 274: 784–787.
[Abstract/Free Full Text] Webster JI, Tonelli L, Sternberg EM (2002) Neuroendocrine regulation of immunity. Annu Rev Immunol 20: 125–163.[Web of Science][Medline]
Wissink S, van Heerde EC, vand der Burg B, van der Saag PT (1998) A dual mechanism mediates repression of NF-kappaB activity by glucocorticoids. Mol Endocrinol 12: 355–363.
[Abstract/Free Full Text]
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