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 Interleukin (IL)-6, But Not IL-1, Induction in the Brain Downstream of Cyclooxygenase-2 Is Essential for the Induction of Febrile Response against Peripheral IL-1α

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5044-5048 ◽  
Author(s):  
Kyoko Kagiwada ◽  
Dai Chida ◽  
Tomoya Sakatani ◽  
Masahide Asano ◽  
Aya Nambu ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Cyclooxygenase 2 ◽  
Signaling Cascade ◽  
Endogenous Pyrogen ◽  
Febrile Response ◽  
Cox 2 ◽  
The Brain ◽  
Deficient Mice

Abstract IL-1 is an endogenous pyrogen produced upon inflammation or infection. Previously, we showed that, upon injection with turpentine, IL-1 is induced in the brain in association with the development of fever. The role of endogenous IL-1 in the brain and the signaling cascade to activate thermosensitive neurons, however, remain to be elucidated. In this report, febrile response was analyzed after peripheral injection of IL-1α. We found that a normal febrile response was induced even in IL-1α/β-deficient mice, indicating that production of IL-1 in the brain is not necessarily required for the response. In contrast, IL-6-deficient mice did not exhibit a febrile response. Cyclooxygenase (Cox)-2 expression in the brain was strongly induced 1.5 h after injection of IL-1α, whereas IL-6 expression was observed 3 h after the injection. Cox-2 expression in the brain was not influenced by IL-6 deficiency, whereas indomethacin, an inhibitor of cyclooxygenases, completely inhibited induction of IL-6. These observations suggest a mechanism of IL-1-induced febrile response in which IL-1 in the blood activates Cox-2, with the resulting prostaglandin E2 inducing IL-6 in the brain, leading to the development of fever.

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 The Role of Interleukin-6 in Lipopolysaccharide-Induced Fever by Mechanisms Independent of Prostaglandin E2

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1850-1860 ◽  
Author(s):  
Camilla Nilsberth ◽  
Louise Elander ◽  
Namik Hamzic ◽  
Maria Norell ◽  
Johanna Lönn ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Knockout Mice ◽  
Cyclooxygenase 2 ◽  
Prostaglandin E ◽  
Wild Type ◽  
Febrile Response ◽  
Prostaglandin E Synthase ◽  
Genotype Difference ◽  
The Relationship

Fever has been shown to be elicited by prostaglandin E2 (PGE2) binding to its receptors on thermoregulatory neurons in the anterior hypothalamus. The signals that trigger PGE2 production are thought to include proinflammatory cytokines, such as IL-6. However, although the presence of IL-6 is critical for fever, IL-6 by itself is not or only weakly pyrogenic. Here we examined the relationship between IL-6 and PGE2 in lipopolysaccharide (LPS)-induced fever. Immune-challenged IL-6 knockout mice did not produce fever, in contrast to wild-type mice, but the expression of the inducible PGE2-synthesizing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase-1, was similarly up-regulated in the hypothalamus of both genotypes, which also displayed similarly elevated PGE2 levels in the cerebrospinal fluid. Nevertheless, both wild-type and knockout mice displayed a febrile response to graded concentrations of PGE2 injected into the lateral ventricle. There was no major genotype difference in the expression of IL-1β and TNFα or their receptors, and pretreatment of IL-6 knockout mice with soluble TNFα receptor ip or intracerebroventricularly or a cyclooxygenase-2 inhibitor ip did not abolish the LPS unresponsiveness. Hence, although IL-6 knockout mice have both an intact PGE2 synthesis and an intact fever-generating pathway downstream of PGE2, endogenously produced PGE2 is not sufficient to produce fever in the absence of IL-6. The findings suggest that IL-6 controls some factor(s) in the inflammatory cascade, which render(s) IL-6 knockout mice refractory to the pyrogenic action of PGE2, or that it is involved in the mechanisms that govern release of synthesized PGE2 onto its target neurons.

scholarly journals Coexpression of Microsomal-Type Prostaglandin E Synthase with Cyclooxygenase-2 in Brain Endothelial Cells of Rats during Endotoxin-Induced Fever

2001 ◽  
Vol 21 (8) ◽  
pp. 2669-2677 ◽  
Author(s):  
Kanato Yamagata ◽  
Kiyoshi Matsumura ◽  
Wataru Inoue ◽  
Takuma Shiraki ◽  
Kyoko Suzuki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cyclooxygenase 2 ◽  
Prostaglandin E ◽  
Brain Endothelial Cells ◽  
Prostaglandin E Synthase

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.

scholarly journals Neural Mechanisms of Inflammation-Induced Fever

2018 ◽  
Vol 24 (4) ◽  
pp. 381-399 ◽  
Author(s):  
Anders Blomqvist ◽  
David Engblom
Keyword(s):  
Peripheral Nerves ◽  
Circumventricular Organs ◽  
Neural Mechanisms ◽  
Prostaglandin E ◽  
Receptor Subtype ◽  
Common Symptom ◽  
Immune Challenge ◽  
Brain Endothelial Cells ◽  
Efferent Limb ◽  
The Brain

Fever is a common symptom of infectious and inflammatory disease. It is well-established that prostaglandin E2 is the final mediator of fever, which by binding to its EP3 receptor subtype in the preoptic hypothalamus initiates thermogenesis. Here, we review the different hypotheses on how the presence of peripherally released pyrogenic substances can be signaled to the brain to elicit fever. We conclude that there is unequivocal evidence for a humoral signaling pathway by which proinflammatory cytokines, through their binding to receptors on brain endothelial cells, evoke fever by eliciting prostaglandin E2 synthesis in these cells. The evidence for a role for other signaling routes for fever, such as signaling via circumventricular organs and peripheral nerves, as well as transfer into the brain of peripherally synthesized prostaglandin E2 are yet far from conclusive. We also review the efferent limb of the pyrogenic pathways. We conclude that it is well established that prostaglandin E2 binding in the preoptic hypothalamus produces fever by disinhibition of presympathetic neurons in the brain stem, but there is yet little understanding of the mechanisms by which factors such as nutritional status and ambient temperature shape the response to the peripheral immune challenge.

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