liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Fever: Role of brain endothelial prostaglandins
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fever and loss of appetite are two of the most fundamental manifestations of disease. These disease symptoms, which lead to deviations from normal body temperature and food intake patterns, are seen in a vast array of infectious and inflammatory conditions. It is known that peripheral signals from the immune system are essential triggers for these responses, which are orchestrated by neuronal circuits in the brain. Due to the blood‐brain barrier, peripheral inflammatory signals require a specific mode of transmission into the brain. Such mechanisms have been proposed, but interventional studies of these mechanisms have never rendered conclusive results. In this thesis, we present the first functional evidence of cyclooxygenase 2 (COX‐2) and microsomal prostaglandin E synthase type 1 (mPGES‐1) mediated prostaglandin E2 synthesis in the blood‐brain barrier endothelial cells as a signaling mechanism in the initiation of inflammatory fever. We also show that one of the world’s most widely used antipyretics, paracetamol, acts by inhibition of COX‐2. Combined with the finding that COX‐2 and mPGES‐1 in brain endothelial cells play a key role in inflammatory fever, this finding suggests that paracetamol inhibits fever by specifically blocking prostaglandin E2 synthesis in blood‐brain barrier endothelium. In another symptom of inflammation, anorexia, the cellular origin of peripheral signals triggering acute anorexia are largely unknown. We show that the expression of myeloid differentiation primary response gene 88 (Myd88) in myeloid cells is important for the initiation of acute inflammatory anorexia and the maintenance of cancer anorexia‐cachexia.

Taken together, these findings provide a significant advancement of our understanding of the mechanisms triggering acute inflammatory fever and anorexia and also explain the antipyretic effect of paracetamol.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. , 58 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1429
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:liu:diva-111727ISBN: 978-91-7519-190-4 (print)OAI: oai:DiVA.org:liu-111727DiVA: diva2:759143
Public defence
2014-12-05, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2014-10-29 Created: 2014-10-29 Last updated: 2017-07-07Bibliographically approved
List of papers
1. Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells
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
Show others...
2013 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 5, 1973-1980 p.Article 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
Keyword
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
2. Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2
Open this publication in new window or tab >>Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2
Show others...
2013 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 71, 124-129 p.Article 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
Keyword
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
3. Deletion of Prostaglandin E-2 Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever
Open this publication in new window or tab >>Deletion of Prostaglandin E-2 Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever
Show others...
2014 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 35, 11684-11690 p.Article 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
Keyword
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: 2017-12-05
4. Cyclooxygenase isoform exchange blocks inflammatory symptoms
Open this publication in new window or tab >>Cyclooxygenase isoform exchange blocks inflammatory symptoms
2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Cyclooxygenase‐2 (COX‐2) is the main source of inducible prostaglandin E2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. In contrast, COX‐1 is dispensable for most inflammatory symptoms. Global deletion of COX‐2 leads to a blockade of inflammation‐induced fever and appetite loss but also to high rates of fetal mortality. The latter is unfortunate since mice without COX‐2 are powerful tools in the study of inflammation and cardiovascular medicine. The differential functionality of the COX isoforms could be due to differences in regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, leading to distinct functional properties of the proteins. To study this in the context of inflammatory symptoms, we used mice in which the coding sequence of COX‐2 was replaced by the corresponding sequence of COX‐1. In these mice, COX‐1 mRNA was induced by inflammation but COX‐1 protein expression did not fully mimic inflammation‐induced COX‐2 expression. Just like mice globally lacking COX‐2, these mice showed a complete lack of fever and inflammation‐induced anorexia. However, as previously reported, they displayed close to normal survival rates. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate inflammatory symptoms, making the line an interesting alternative to COX‐2 knockouts for the study of inflammation. Our results also show that the functional differences between COX‐1 and COX‐2 in the context of inflammatory symptoms is not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels, which make hybrid genes less functional.

National Category
Cell Biology Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-111725 (URN)
Available from: 2014-10-29 Created: 2014-10-29 Last updated: 2015-11-06Bibliographically approved

Open Access in DiVA

omslag(7696 kB)40 downloads
File information
File name COVER01.pdfFile size 7696 kBChecksum SHA-512
b0f5ba9bdd3f86f0791e73abf93a6a5f2f14bc9943c4b058ac2d956b0212f07178dd09706f0976218fb5ab69a70fa73173c08f75760803e790c6349e746b1180
Type coverMimetype application/pdf

Authority records BETA

Björk Wilhelms, Daniel

Search in DiVA

By author/editor
Björk Wilhelms, Daniel
By organisation
Division of Cell BiologyFaculty of Health Sciences
Cell Biology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 821 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf