Attenuated fever in pregnant rats is associated with blunted syntheses of brain cyclooxygenase-2 and PGE2

2002 ◽  
Vol 283 (6) ◽  
pp. R1346-R1353 ◽  
Author(s):  
Kyoko Imai-Matsumura ◽  
Kiyoshi Matsumura ◽  
Akira Terao ◽  
Yasuyoshi Watanabe
Keyword(s):  
Endothelial Cells ◽  
Cyclooxygenase 2 ◽  
Female Rats ◽  
Brain Endothelial Cells ◽  
Term Pregnancy ◽  
Pregnant Rats ◽  
Near Term ◽  
Fever Response ◽  
Colonic Temperature ◽  
The Brain

Attenuation of fever occurs in pregnant animals. This study examined a hypothesis that brain production of PGE2, the final mediator of fever, is suppressed in pregnant animals. Near-term pregnant rats and age-matched nonpregnant female rats were injected with lipopolysaccharide (100 μg/kg) intraperitoneally. Four hours later, colonic temperature was measured, their cerebrospinal fluid (CSF) was sampled for PGE2 assay, and their brains were processed for immunohistochemistry of cyclooxygenase-2, an enzyme involved in PGE2 biosynthesis. In the pregnant rats, lipopolysaccharide injection resulted in significantly smaller elevations in both colonic temperature and CSF-PGE2 level than in nonpregnant rats. In the pregnant rats, lipopolysaccharide-induced cyclooxygenase-2 expression was blunted in terms of the number of positive cells. There was a significant correlation between PGE2 level in CSF and the number of cyclooxygenase-2-positive endothelial cells. These results suggest that suppressed PGE2 production in the brain is one cause for the attenuated fever response at near-term pregnancy and that this suppressed PGE2 production is due to the suppressed induction of cyclooxygenase-2 in brain endothelial cells.

scholarly journals Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells

Endocrinology ◽  
2012 ◽  
Vol 153 (10) ◽  
pp. 4849-4861 ◽  
Author(s):  
Linda Engström ◽  
Johan Ruud ◽  
Anna Eskilsson ◽  
Anders Larsson ◽  
Ludmila Mackerlova ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cerebrospinal Fluid ◽  
Prostaglandin E2 ◽  
Hematopoietic Cells ◽  
Cyclooxygenase 2 ◽  
Prostaglandin E ◽  
Brain Endothelial Cells ◽  
Febrile Response ◽  
Pge2 Synthesis ◽  
The Brain

Abstract Immune-induced prostaglandin E2 (PGE2) synthesis is critical for fever and other centrally elicited disease symptoms. The production of PGE2 depends on cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1), but the identity of the cells involved has been a matter of controversy. We generated mice expressing mPGES-1 either in cells of hematopoietic or nonhematopoietic origin. Mice lacking mPGES-1 in hematopoietic cells displayed an intact febrile response to lipopolysaccharide, associated with elevated levels of PGE2 in the cerebrospinal fluid. In contrast, mice that expressed mPGES-1 only in hematopoietic cells, although displaying elevated PGE2 levels in plasma but not in the cerebrospinal fluid, showed no febrile response to lipopolysaccharide, thus pointing to the critical role of brain-derived PGE2 for fever. Immunohistochemical stainings showed that induced cyclooxygenase-2 expression in the brain exclusively occurred in endothelial cells, and quantitative PCR analysis on brain cells isolated by flow cytometry demonstrated that mPGES-1 is induced in endothelial cells and not in vascular wall macrophages. Similar analysis on liver cells showed induced expression in macrophages and not in endothelial cells, pointing at the distinct role for brain endothelial cells in PGE2 synthesis. These results identify the brain endothelial cells as the PGE2-producing cells critical for immune-induced fever.

scholarly journals TAK1 in brain endothelial cells mediates fever and lethargy

2011 ◽  
Vol 208 (13) ◽  
pp. 2615-2623 ◽  
Author(s):  
Dirk A. Ridder ◽  
Ming-Fei Lang ◽  
Sergei Salinin ◽  
Jan-Peter Röderer ◽  
Marcel Struss ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sickness Behavior ◽  
Brain Endothelial Cells ◽  
Brain Endothelium ◽  
Endogenous Pyrogen ◽  
Inflammatory Stimuli ◽  
Cox 2 ◽  
Fever Response ◽  
The Brain ◽  
Pituitary Adrenal Axis

Systemic inflammation affects the brain, resulting in fever, anorexia, lethargy, and activation of the hypothalamus–pituitary–adrenal axis. How peripheral inflammatory signals reach the brain is still a matter of debate. One possibility is that, in response to inflammatory stimuli, brain endothelial cells in proximity to the thermoregulatory centers produce cyclooxygenase 2 (COX-2) and release prostaglandin E2, causing fever and sickness behavior. We show that expression of the MAP kinase kinase kinase TAK1 in brain endothelial cells is needed for interleukin 1β (IL-1β)–induced COX-2 production. Exploiting the selective expression of the thyroxine transporter Slco1c1 in brain endothelial cells, we generated a mouse line allowing inducible deletion of Tak1 specifically in brain endothelium. Mice lacking the Tak1 gene in brain endothelial cells showed a blunted fever response and reduced lethargy upon intravenous injection of the endogenous pyrogen IL-1β. In conclusion, we demonstrate that TAK1 in brain endothelial cells induces COX-2, most likely by activating p38 MAPK and c-Jun, and is necessary for fever and sickness behavior.

Signaling the brain in systemic inflammation: which vagal branch is involved in fever genesis?

1998 ◽  
Vol 275 (1) ◽  
pp. R63-R68 ◽  
Author(s):  
Christopher T. Simons ◽  
Vladimir A. Kulchitsky ◽  
Naotoshi Sugimoto ◽  
Louis D. Homer ◽  
Miklos Székely ◽  
...  
Keyword(s):  
Vagal Afferents ◽  
Male Wistar Rats ◽  
Food Retention ◽  
Maximal Rise ◽  
Fever Response ◽  
Colonic Temperature ◽  
Postsurgical Recovery ◽  
The Brain ◽  
Bladder Urine

Recent evidence has suggested a role of abdominal vagal afferents in the pathogenesis of the febrile response. The abdominal vagus consists of five main branches (viz., the anterior and posterior celiac branches, anterior and posterior gastric branches, and hepatic branch). The branch responsible for transducing a pyrogenic signal from the periphery to the brain has not as yet been identified. In the present study, we address this issue by testing the febrile responsiveness of male Wistar rats subjected to one of four selective vagotomies: celiac (CBV), gastric (GBV), hepatic (HBV), or sham (SV). In the case of CBV, GBV, and HBV, only the particular vagal branch(es) was cut; for SV, all branches were left intact. After the postsurgical recovery (26–29 days), the rats had a catheter implanted into the jugular vein. On days 29–32, their colonic temperature (Tc) responses to a low dose (1 μg/kg) of Escherichia colilipopolysaccharide (LPS) were studied. Three days later, the animals were subjected to a 24-h food and water deprivation, and the effectiveness of the four vagotomies to induce gastric food retention, pancreatic hypertrophy, and impairment of the portorenal osmotic reflex was assessed by weighing the stomach and pancreas and measuring the specific gravity of bladder urine, respectively. Stomach mass, pancreas mass, and urine density successfully separated the four experimental groups into four distinct clusters, thus confirming that each type of vagotomy had a different effect on the indexes measured. The Tc responses of SV, CBV, and GBV rats to LPS did not differ and were characterized by a latency of ∼40 min and a maximal rise of 0.7 ± 0.1, 0.6 ± 0.1, and 0.9 ± 0.2°C, respectively. The fever response of the HBV rats was different; practically no Tc rise occurred (0.1 ± 0.2°C). The HBV appeared to be the only selective abdominal vagotomy affecting the febrile responsiveness. We conclude, therefore, that the hepatic vagus plays an important role in the transduction of a pyrogenic signal from the periphery to the brain.

scholarly journals Two peptides targeting endothelial receptors are internalized into murine brain endothelial cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249686
Author(s):  
Diána Hudecz ◽  
Sara Björk Sigurdardóttir ◽  
Sarah Christine Christensen ◽  
Casper Hempel ◽  
Andrew J. Urquhart ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transferrin Receptor ◽  
Vesicular Transport ◽  
Brain Diseases ◽  
Brain Endothelial Cells ◽  
Binding Studies ◽  
Wide Range ◽  
Murine Brain ◽  
The Brain

The blood-brain barrier (BBB) is one of the main obstacles for therapies targeting brain diseases. Most macromolecules fail to pass the tight BBB, formed by brain endothelial cells interlinked by tight junctions. A wide range of small, lipid-soluble molecules can enter the brain parenchyma via diffusion, whereas macromolecules have to transcytose via vesicular transport. Vesicular transport can thus be utilized as a strategy to deliver brain therapies. By conjugating BBB targeting antibodies and peptides to therapeutic molecules or nanoparticles, it is possible to increase uptake into the brain. Previously, the synthetic peptide GYR and a peptide derived from melanotransferrin (MTfp) have been suggested as candidates for mediating transcytosis in brain endothelial cells (BECs). Here we study uptake, intracellular trafficking, and translocation of these two peptides in BECs. The peptides were synthesized, and binding studies to purified endocytic receptors were performed using surface plasmon resonance. Furthermore, the peptides were conjugated to a fluorophore allowing for live-cell imaging studies of their uptake into murine brain endothelial cells. Both peptides bound to low-density lipoprotein receptor-related protein 1 (LRP-1) and the human transferrin receptor, while lower affinity was observed against the murine transferrin receptor. The MTfp showed a higher binding affinity to all receptors when compared to the GYR peptide. The peptides were internalized by the bEnd.3 mouse endothelial cells within 30 min of incubation and frequently co-localized with endo-lysosomal vesicles. Moreover, our in vitro Transwell translocation experiments confirmed that GYR was able to cross the murine barrier and indicated the successful translocation of MTfp. Thus, despite binding to endocytic receptors with different affinities, both peptides are able to transcytose across the murine BECs.

Fos expression in brain stem nuclei of pregnant rats after hydralazine-induced hypotension

1999 ◽  
Vol 277 (2) ◽  
pp. R532-R540 ◽  
Author(s):  
Kathleen S. Curtis ◽  
J. Thomas Cunningham ◽  
Cheryl M. Heesch
Keyword(s):  
Area Postrema ◽  
Virgin Female ◽  
Female Rats ◽  
Ventrolateral Medulla ◽  
Pregnant Rats ◽  
Induced Hypotension ◽  
Central Response ◽  
Vehicle Treatment ◽  
Fos Expression ◽  
The Brain

Fos and dopamine β-hydroxylase immunoreactivity were evaluated in the brain stems of 21-day pregnant and virgin female rats injected with either hydralazine (HDZ; 10 mg/kg iv) or vehicle. HDZ produced significant hypotension in both groups, although baseline blood pressure was lower in pregnant rats (96 ± 2.5 mmHg) than in virgin female rats (121 ± 2.8 mmHg). There were no differences in Fos immunoreactivity in the brain stems of pregnant and virgin female rats after vehicle treatment. HDZ-induced hypotension significantly increased Fos expression in both groups; however, the magnitude of the increases differed in the caudal ventrolateral medulla (CVL), the area postrema (AP), and the rostral ventrolateral medulla (RVL). Fos expression after HDZ in pregnant rats was augmented in noncatecholaminergic neurons of the CVL but was attenuated in the AP and in noncatecholaminergic neurons in the RVL. These results are consistent with differences in the sympathetic response to hypotension between pregnant and virgin female rats and indicate that the central response to hypotension may be different in pregnant rats.

scholarly journals Endogenous THBD (Thrombomodulin) Mediates Angiogenesis in the Ischemic Brain—Brief Report

2020 ◽  
Vol 40 (12) ◽  
pp. 2837-2844 ◽  
Author(s):  
Jan Wenzel ◽  
Dimitrios Spyropoulos ◽  
Julian Christopher Assmann ◽  
Mahtab Ahmad Khan ◽  
Ines Stölting ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Soluble Form ◽  
Stroke Outcome ◽  
Brain Endothelial Cells ◽  
Ischemic Brain ◽  
Infarct Area ◽  
The Brain

Objective: THBD (thrombomodulin) is part of the anticoagulant protein C-system that acts at the endothelium and is involved in anti-inflammatory and barrier-stabilizing processes. A recombinant soluble form of THBD was shown to have protective effects in different organs, but how the endogenous THBD is regulated during ischemia, particularly in the brain is not known to date. The aim of this study was to investigate the role of THBD, especially in brain endothelial cells, during ischemic stroke. Approach and Results: To induce ischemic brain damage, we occluded the middle cerebral artery of mice. We found an increased endothelial expression of Thbd in the peri-infarct area, whereas in the core of the ischemic tissue Thbd expression was decreased compared with the contralateral side. We generated a novel Cre/loxP-based mouse line that allows for the inducible deletion of Thbd specifically in brain endothelial cells, which worsened stroke outcome 48 hours after middle cerebral artery occlusion. Unexpectedly, we found no signs of increased coagulation, thrombosis, or inflammation in the brain but decreased vessel diameters and impaired angiogenesis in the peri-infarct area that led to a reduced overall vessel length 1 week after stroke induction. Conclusions: Endogenous THBD acts as a protective factor in the brain during ischemic stroke and enhances vessel diameter and proliferation. These previously unknown properties of THBD could offer new opportunities to affect vessel function after ischemia and thereby improve stroke outcome.

scholarly journals Interaction between Endothelial Protein C Receptor and Intercellular Adhesion Molecule 1 to Mediate Binding of Plasmodium falciparum -Infected Erythrocytes to Endothelial Cells

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Marion Avril ◽  
Maria Bernabeu ◽  
Maxwell Benjamin ◽  
Andrew Jay Brazier ◽  
Joseph D. Smith
Keyword(s):  
Endothelial Cells ◽  
Cerebral Malaria ◽  
Intercellular Adhesion Molecule ◽  
Brain Endothelial Cells ◽  
Endothelial Protein C Receptor ◽  
Intercellular Adhesion Molecule 1 ◽  
Cd36 Expression ◽  
Tnf Α ◽  
Group A ◽  
The Brain

ABSTRACT Intercellular adhesion molecule 1 (ICAM-1) and the endothelial protein C receptor (EPCR) are candidate receptors for the deadly complication cerebral malaria. However, it remains unclear if Plasmodium falciparum parasites with dual binding specificity are involved in cytoadhesion or different parasite subpopulations bind in brain microvessels. Here, we investigated this issue by studying different subtypes of ICAM-1-binding parasite lines. We show that two parasite lines expressing domain cassette 13 (DC13) of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family have dual binding specificity for EPCR and ICAM-1 and further mapped ICAM-1 binding to the first DBLβ domain following the PfEMP1 head structure in both proteins. As PfEMP1 head structures have diverged between group A (EPCR binders) and groups B and C (CD36 binders), we also investigated how ICAM-1-binding parasites with different coreceptor binding traits influence P. falciparum -infected erythrocyte binding to endothelial cells. Whereas levels of binding to tumor necrosis factor alpha (TNF-α)-stimulated endothelial cells from the lung and brain by all ICAM-1-binding parasite lines increased, group A (EPCR and ICAM-1) was less dependent than group B (CD36 and ICAM-1) on ICAM-1 upregulation. Furthermore, both group A DC13 parasite lines had higher binding levels to brain endothelial cells (a microvascular niche with limited CD36 expression). This study shows that ICAM-1 is a coreceptor for a subset of EPCR-binding parasites and provides the first evidence of how EPCR and ICAM-1 interact to mediate parasite binding to both resting and TNF-α-activated primary brain and lung endothelial cells. IMPORTANCE Cerebral malaria is a severe neurological complication of P. falciparum infection associated with infected erythrocyte (IE) binding in cerebral vessels. Yet little is known about the mechanisms by which parasites adhere in the brain or other microvascular sites. Here, we studied parasite lines expressing group A DC13-containing PfEMP1 variants, a subset that has previously been shown to have high brain cell- and other endothelial cell-binding activities. We show that DC13-containing PfEMP1 variants have dual EPCR- and ICAM-1-binding activities and that both receptors are involved in parasite adherence to lung and brain endothelial cells. As both EPCR and ICAM-1 are implicated in cerebral malaria, these findings suggest the possibility that parasites with dual binding activities are involved in parasite sequestration to microvascular beds with low CD36 expression, such as the brain, and we urge more research into the multiadhesive properties of PfEMP1 variants.

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