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Eskilsson, Anna
Publications (10 of 12) Show all publications
Eskilsson, A. (2020). Inflammatory Signaling Across the Blood-Brain Barrier and the Generation of Fever. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Inflammatory Signaling Across the Blood-Brain Barrier and the Generation of Fever
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fever is a cardinal sign of inflammation and is evolutionary conserved. Fever is known to be beneficial during acute inflammation, but over time and if very high it can be detrimental. The signaling pathways by which fever is initiated by the brain and the peripheral mechanisms through which the temperature increase is generated were studied from several point of views. Fever is known to be dependent on prostaglandin E2 (PGE2) binding to its receptors in the median preoptic nucleus of the hypothalamus, which signals to the brainstem and through sympathetic nerves to heat conserving and heat producing effector organs. This thesis focuses on identifying the cells that produce the PGE2 critical for the fever response; showing where in the brain the critical PGE2 production takes place; demonstrating how peripheral inflammation activates these cells to produce PGE2; and finally, identifying the effector mechanisms behind the temperature elevation in fever. By using a newly developed specific antibody we showed that the enzyme responsible for the terminal step in the production of PGE2, microsomal prostaglandin E-synthase 1 (mPGES-1), is expressed in endothelial cells of brain blood vessels in mice where it is co-expressed with the enzyme cyclooxygenase-2 (Cox-2), which is known to be induced in these cells and to be rate limiting for the PGE2 production. The mPGES-1 enzyme was also expressed in several other cell types and structures which however did not express Cox-2, such as capillary-associated pericytes, astroglial cells, leptomeninges, and the choroid plexus. The role of the mPGES-1 in these other cells/structures remains unknown. Next, by using mice with selective deletion of Cox-2 in brain endothelial cells, we showed that local PGE2 production in deep brain areas, such as the hypothalamus, is critical for the febrile response to peripheral inflammation. In contrast, PGE2 production in other brain areas and the overall PGE2 level in the brain were not critical for the febrile response. Partly restoring the PGE2 synthesizing capacity in the anterior hypothalamus of mice lacking such capacity with a lentiviral vector resulted in a temperature elevation in response to an intraperitoneal injection of bacterial wall lipopolysaccharide (LPS). The data show that the febrile response is dependent on the local release of PGE2 onto its target neurons, possibly by a paracrine mechanism. Deletion of the receptor for the pyrogenic cytokine IL-6 on brain endothelial cells, but not on neurons or peripheral nerves, strongly attenuated the febrile response to LPS and reduced the induction of the Cox-2 expression in the hypothalamus. Furthermore, mice deficient of the IL- 6Rα gene in the brain endothelial cells showed a reduced SOCS3 mRNA induction, whereas IκB mRNA-levels were unaffected, suggesting that the IL-6 signaling occurs via STAT3 activation and not signaling through the transcription factor NF-κB. This idea was confirmed by the observation of attenuated fever in mice deficient of STAT3 in brain endothelial cells. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R on brain endothelial cells to induce prostaglandin synthesis in these cells. Finally, we demonstrate that mice with genetic deletion of uncoupling protein-1 (UCP-1), hence lacking functional brown adipose tissue, had a normal fever response to LPS, and that LPS caused no activation of brown adipose tissue in wild type mice. However, blocking peripheral cutaneous vasoconstriction resulted in a blunted fever response to LPS, suggesting that heat conservation, possibly together with shivering or non-shivering thermogenesis in the musculature, is responsible for the generation of immune-induced fever, whereas brown adipose tissue thermogenesis is not involved.  

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2020. p. 44
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1724
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-163003 (URN)10.3384/diss.diva-163003 (DOI)9789179299361 (ISBN)
Public defence
2020-02-14, Hasselqvistsalen, Building 511 Campus US, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-01-24Bibliographically approved
Matsuwaki, T., Shionoya, K., Ihnatko, R., Eskilsson, A., Kakuta, S., Dufour, S., . . . Blomqvist, A. (2017). Involvement of interleukin-1 type 1 receptors in lipopolysaccharide-induced sickness responses. Brain, behavior, and immunity, 66, 165-176
Open this publication in new window or tab >>Involvement of interleukin-1 type 1 receptors in lipopolysaccharide-induced sickness responses
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2017 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 66, p. 165-176Article in journal (Refereed) Published
Abstract [en]

Sickness responses to lipopolysaccharide (LPS) were examined in mice with deletion of the interleukin (IL)-1 type 1 receptor (IL-1R1). IL-1R1 knockout (1(0) mice displayed intact anorexia and HPA-axis activation to intraperitoneally injected LPS (anorexia: 10 or 120 mu g/kg; HPA-axis: 120 mu g/kg), but showed attenuated but not extinguished fever (120 g/kg). Brain PGE2 synthesis was attenuated, but Cox-2 induction remained intact. Neither the tumor necrosis factor-alpha (TNF alpha) inhibitor etanercept nor the IL -6 receptor antibody tocilizumab abolished the LPS induced fever in IL -1R1 KO mice. Deletion of IL -1R1 specifically in brain endothelial cells attenuated the LPS induced fever, but only during the late, 3rd phase of fever, whereas deletion of IL-1R1 on neural cells or on peripheral nerves had little or no effect on the febrile response. We conclude that while IL-1 signaling is not critical for LPS induced anorexia or stress hormone release, IL-1R1, expressed on brain endothelial cells, contributes to the febrile response to LPS. However, also in the absence of IL-1R1, LPS evokes a febrile response, although this is attenuated. This remaining fever seems not to be mediated by IL-6 receptors or TNFa, but by some yet unidentified pyrogenic factor. 

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Interleukin-1 type 1 receptor; Lipopolysaccharide; Fever; Anorexia; ACTH; Corticosterone; Endothelial cells; THF alpha; Interleukin-6; PGE(2)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-143084 (URN)10.1016/j.bbi.2017.06.013 (DOI)000414236600018 ()28655587 (PubMedID)
Note

Funding Agencies|Japan Society for the Promotion of Science [15K18800]; Swedish Research Council [20725, 07879]; Knut and Alice Wallenberg foundation; Swedish Brain Foundation; Swedish Cancer Foundation [213/692]; County Council of Ostergotland; Sixth Research Framework Programme of the European Union, Project MUGEN [MUGEN LSHG-CT-2005-005203]; MRC research grant [G0801296]

Available from: 2017-11-22 Created: 2017-11-22 Last updated: 2018-06-18
Wilhelms, D. B., Kirilov, M., Mirrasekhian, E., Eskilsson, A., Örtegren Kugelberg, U., Klar, C., . . . Engblom, D. (2014). Deletion of Prostaglandin E-2 Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever. Journal of Neuroscience, 34(35), 11684-11690
Open this publication in new window or tab >>Deletion of Prostaglandin E-2 Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever
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2014 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 35, p. 11684-11690Article in journal (Refereed) Published
Abstract [en]

Fever is a hallmark of inflammatory and infectious diseases. The febrile response is triggered by prostaglandin E-2 synthesis mediated by induced expression of the enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1). The cellular source for pyrogenic PGE(2) remains a subject of debate; several hypotheses have been forwarded, including immune cells in the periphery and in the brain, as well as the brain endothelium. Here we generated mice with selective deletion of COX-2 and mPGES1 in brain endothelial cells. These mice displayed strongly attenuated febrile responses to peripheral immune challenge. In contrast, inflammation-induced hypoactivity was unaffected, demonstrating the physiological selectivity of the response to the targeted gene deletions. These findings demonstrate that PGE(2) synthesis in brain endothelial cells is critical for inflammation-induced fever.

Place, publisher, year, edition, pages
Society for Neuroscience, 2014
Keywords
COX-2; endothelium; fever; mPGES-1; PGE(2); prostaglandin
National Category
Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:liu:diva-111281 (URN)10.1523/JNEUROSCI.1838-14.2014 (DOI)000341314900017 ()25164664 (PubMedID)
Note

Funding Agencies|Swedish Medical Research Council; Swedish Cancer Foundation; European Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County Council of stergotland; Wenner-Gren Fellowship

Available from: 2014-10-14 Created: 2014-10-14 Last updated: 2018-01-11
Eskilsson, A., Tachikawa, M., Hosoya, K.-I. & Blomqvist, A. (2014). Distribution of microsomal prostaglandin E synthase-1 in the mouse brain. Journal of Comparative Neurology, 522(14), 3229-3244
Open this publication in new window or tab >>Distribution of microsomal prostaglandin E synthase-1 in the mouse brain
2014 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 522, no 14, p. 3229-3244Article in journal (Refereed) Published
Abstract [en]

Previous studies in rats have demonstrated that microsomal prostaglandin E synthase-1 (mPGES-1) is induced in brain vascular cells that also express inducible cyclooxygenase-2, suggesting that such cells are the source of the increased PGE2 levels that are seen in the brain following peripheral immune stimulation, and that are associated with sickness responses such as fever, anorexia, and stress hormone release. However, while most of what is known about the functional role of mPGES-1 for these centrally evoked symptoms is based on studies on genetically modified mice, the cellular localization of mPGES-1 in the mouse brain has not been thoroughly determined. Here, using a newly developed antibody that specifically recognizes mouse mPGES-1 and dual-labeling for cell-specific markers, we report that mPGES-1 is constitutively expressed in the mouse brain, being present not only in brain endothelial cells, but also in several other cell types and structures, such as capillary-associated pericytes, astroglial cells, leptomeninges, and the choroid plexus. Regional differences were seen with particularly prominent labeling in autonomic relay structures such as the area postrema, the subfornical organ, the paraventricular hypothalamic nucleus, the arcuate nucleus, and the preoptic area. Following immune stimulation, mPGES-1 in brain endothelial cells, but not in other mPGES-1-positive cells, was coexpressed with cyclooxygenase-2, whereas there was no coexpression between mPGES-1 and cyclooxygenase-1. These data imply a widespread synthesis of PGE2 or other mPGES-1-dependent products in the mouse brain that may be related to inflammation-induced sickness symptom as well as other functions, such as blood flow regulation.

Place, publisher, year, edition, pages
John Wiley & Sons, 2014
Keywords
Astroglial cells; Cyclooxygenase; Endothelial cells; Immune challenge; Pericytes; Prostaglandin synthesis
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-109962 (URN)10.1002/cne.23593 (DOI)000339967300006 ()24668417 (PubMedID)2-s2.0-84904553311 (Scopus ID)
Available from: 2014-09-12 Created: 2014-08-29 Last updated: 2020-01-08
Eskilsson, A., Mirrasekhian, E., Dufour, S., Schwaninger, M., Engblom, D. & Blomqvist, A. (2014). Immune-Induced Fever Is Mediated by IL-6 Receptors on Brain Endothelial Cells Coupled to STAT3-Dependent Induction of Brain Endothelial Prostaglandin Synthesis. Journal of Neuroscience, 34(48), 15957-15961
Open this publication in new window or tab >>Immune-Induced Fever Is Mediated by IL-6 Receptors on Brain Endothelial Cells Coupled to STAT3-Dependent Induction of Brain Endothelial Prostaglandin Synthesis
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2014 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 48, p. 15957-15961Article in journal (Refereed) Published
Abstract [en]

The cytokine IL-6, which is released upon peripheral immune challenge, is critical for the febrile response, but the mechanism by which IL-6 is pyrogenic has remained obscure. Herewegenerated mice with deletion of themembranebound IL-6 receptor alpha (IL-6R alpha) onneural cells, on peripheral nerves, on fine sensory afferent fibers, and on brain endothelial cells, respectively, and examined its role for the febrile response to peripherally injected lipopolysaccharide. We show that IL-6R alpha on neural cells, peripheral nerves, and fine sensory afferents are dispensable for the lipopolysaccharide-induced fever, whereas IL-6R alpha in the brain endothelium plays an important role. Hence deletion of IL-6R alpha on brain endothelial cells strongly attenuated the febrile response, and also led to reduced induction of the prostaglandin synthesizing enzyme Cox-2 in the hypothalamus, the temperature-regulating center in the brain, as well as reduced expression of SOCS3, suggesting involvement of the STAT signaling pathway. Furthermore, deletion of STAT3 in the brain endothelium also resulted in attenuated fever. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R alpha on brain endothelial cells to induce prostaglandin synthesis in these cells, probably in concerted action with other peripherally released cytokines.

Place, publisher, year, edition, pages
Society for Neuroscience, 2014
Keywords
blood-brain barrier; cell-specific gene deletions; fever; interleukin-6; prostaglandins; STAT3
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-113199 (URN)10.1523/JNEUROSCI.3520-14.2014 (DOI)000345923600013 ()25429137 (PubMedID)
Note

Funding Agencies|Swedish Medical Research Council; Swedish Cancer Foundation; European Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County CouncilO Ostergotland

Available from: 2015-01-13 Created: 2015-01-12 Last updated: 2020-01-08
Matsuwaki, T., Eskilsson, A., Örtegren Kugelberg, U., Jönsson, J.-I. & Blomqvist, A. (2014). Interleukin-1 beta induced activation of the hypothalamus-pituitary-adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells. Brain, behavior, and immunity, 40, 166-173
Open this publication in new window or tab >>Interleukin-1 beta induced activation of the hypothalamus-pituitary-adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells
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2014 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 40, p. 166-173Article in journal (Refereed) Published
Abstract [en]

The proinflammatory cytokine interleukin-1 beta (IL-beta) plays a major role in the signal transduction of immune stimuli from the periphery to the central nervous system, and has been shown to be an important mediator of the immune-induced stress hormone release. The signaling pathway by which IL-1 beta exerts this function involves the blood-brain-barrier and induced central prostaglandin synthesis, but the identity of the blood-brain-barrier cells responsible for this signal transduction has been unclear, with both endothelial cells and perivascular macrophages suggested as critical components. Here, using an irradiation and transplantation strategy, we generated mice expressing IL-1 type 1 receptors (IL-1 RI) either in hematopoietic or non-hematopoietic cells and subjected these mice to peripheral immune challenge with IL-beta. Following both intraperitoneal and intravenous administration of IL-beta, mice lacking IL-1R1 in hematopoietic cells showed induced expression of the activity marker c-Fos in the paraventricular hypothalamic nucleus, and increased plasma levels of ACTH and corticosterone. In contrast, these responses were not observed in mice with IL-1R1 expression only in hematopoietic cells. Immunoreactivity for IL-1R1 was detected in brain vascular cells that displayed induced expression of the prostaglandin synthesizing enzyme cyclooxygenase-2 and that were immunoreactive for the endothelial cell marker CD31, but was not seen in cells positive for the brain macrophage marker CD206. These results imply that activation of the HPA-axis by IL-1 beta is dependent on IL-1R1 s on non-hematopoietic cells, such as brain endothelial cells, and that IL-1R1 on perivascular macrophages are not involved.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
HPA-axis Corticosterone; ACTH c-Fos Paraventricular nucleus; Chimeric mice; Bone marrow transplantation; Brain endothelial cells; Perivascular macrophages; Cyclooxygenase-2
National Category
Clinical Medicine Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:liu:diva-109874 (URN)10.1016/j.bbi.2014.03.015 (DOI)000339458400019 ()24681250 (PubMedID)
Note

Funding Agencies|Swedish Research Council [61X-078979]; Swedish Cancer Foundation [13 0295]; County Council of Ostergotland; JSPS [H24-451]

Available from: 2014-08-28 Created: 2014-08-28 Last updated: 2018-01-11
Engström, L., Björk, D., Eskilsson, A., Vasilache, A.-M., Elander, L., Engblom, D. & Blomqvist, A. (2013). Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2. Neuropharmacology, 71, 124-129
Open this publication in new window or tab >>Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2
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2013 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 71, p. 124-129Article in journal (Refereed) Published
Abstract [en]

Acetaminophen is one of the world's most commonly used drugs to treat fever and pain, yet its mechanism of action has remained unclear. Here we tested the hypothesis that acetaminophen blocks fever through inhibition of cyclooxygenase-2 (Cox-2), by monitoring lipopolysaccharide induced fever in mice with genetic manipulations of enzymes in the prostaglandin cascade. We exploited the fact that lowered levels of a specific enzyme make the system more sensitive to any further inhibition of the same enzyme. Mice were immune challenged by an intraperitoneal injection of bacterial wall lipopolysaccharide and their body temperature recorded by telemetry. We found that mice heterozygous for Cox-2, but not for microsomal prostaglandin E synthase-1 (mPGES-1), displayed attenuated fever, indicating a rate limiting role of Cox-2. We then titrated a dose of acetaminophen that did not inhibit the lipopolysaccharide-induced fever in wild-type mice. However, when the same dose of acetaminophen was given to Cox-2 heterozygous mice, the febrile response to lipopolysaccharide was strongly attenuated, resulting in an almost normalized temperature curve, whereas no difference was seen between wild-type and heterozygous mPGES-1 mice. Furthermore, the fever to intracerebrally injected prostaglandin E2 was unaffected by acetaminophen treatment. These findings reveal that acetaminophen, similar to aspirin and other non-steroidal anti-inflammatory drugs, is antipyretic by inhibiting cyclooxygenase-2, and not by inhibiting mPGES-1 or signaling cascades downstream of prostaglandin E2.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Fever; Cyclooxygenase-2; Cyclooxygenase-1; Microsomal prostaglandin E synthase-1; Gene dosage; Hypothalamus
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96170 (URN)10.1016/j.neuropharm.2013.03.012 (DOI)000320424200012 ()
Available from: 2013-08-14 Created: 2013-08-14 Last updated: 2017-12-06
Ruud, J., Björk, D., Nilsson, A., Eskilsson, A., Tang, Y.-j., Stroehle, P., . . . Blomqvist, A. (2013). Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells. The FASEB Journal, 27(5), 1973-1980
Open this publication in new window or tab >>Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells
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2013 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 5, p. 1973-1980Article in journal (Refereed) Published
Abstract [en]

Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

Place, publisher, year, edition, pages
Federation of American Society of Experimental Biology (FASEB), 2013
Keywords
lipopolysaccharide; methylcholanthrene-induced sarcoma; food intake; chimeric mice; Cre-LoxP; inducible cell-specific deletion
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96147 (URN)10.1096/fj.12-225433 (DOI)000318226100017 ()
Available from: 2013-08-14 Created: 2013-08-14 Last updated: 2017-12-06
Hamzik, N., Tang, Y.-j., Eskilsson, A., Örtegren Kugelberg, U., Ruud, J., Jönsson, J.-I., . . . Nilsberth, C. (2013). Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response. Brain, behavior, and immunity, 33, 123-130
Open this publication in new window or tab >>Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response
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2013 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 33, p. 123-130Article in journal (Refereed) Published
Abstract [en]

Interleukin-6 (IL-6) is critical for the lipopolysaccharide (LPS)-induced febrile response. However, the exact source(s) of IL-6 involved in regulating the LPS-elicited fever is still to be identified. One known source of IL-6 is hematopoietic cells, such as monocytes. To clarify the contribution of hematopoietically derived IL-6 to fever, we created chimeric mice expressing IL-6 selectively either in cells of hematopoietic or, conversely, in cells of non-hematopoietic origin. This was performed by extinguishing hematopoietic cells in wild-type (WT) or IL-6 knockout (IL-6 KO) mice by whole-body irradiation and transplanting them with new stem cells. Mice on a WT background but lacking IL-6 in hematopoietic cells displayed normal fever to LPS and were found to have similar levels of IL-6 protein in the cerebrospinal fluid (CSF) and in plasma and of IL-6 mRNA in the brain as WT mice. In contrast, mice on an IL-6 KO background, but with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on a WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of non-hematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Interleukin-6, Hematopoietic cells, Bone marrow transplantation, Fever
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-99401 (URN)10.1016/j.bbi.2013.06.006 (DOI)000324788300016 ()
Note

Funding Agencies|Swedish Research Council|33X-0787968X-2053564X-21463|Swedish Cancer Foundation|4095|Swedish Brain Foundation||Tore Nilsson Foundation||Ake Wiberg Foundation||Langmanska Kulturfonden||Lars Hierta Memorial Foundation||Magn. Bergvall Foundation||County Council of Ostergotland||Harald and Greta Jeansson Foundation||Royal Swedish Academy of Sciences||Foundation of the National Board of Health and Welfare||

Available from: 2013-10-17 Created: 2013-10-17 Last updated: 2017-12-06
Engström, L., Ruud, J., Eskilsson, A., Larsson, A., Mackerlova, L., Kugelberg, U., . . . Blomqvist, A. (2012). Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells. Endocrinology, 153(10), 4849-4861
Open this publication in new window or tab >>Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells
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2012 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, no 10, p. 4849-4861Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Endocrine Society, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84885 (URN)10.1210/en.2012-1375 (DOI)000309210200027 ()
Note

Funding Agencies|Swedish Research Council|7879|Swedish Cancer Foundation|100533|Swedish Brain Foundation||Gustav V:s 80-ars Fond||

Available from: 2012-11-01 Created: 2012-10-26 Last updated: 2017-12-07
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