Brain Endothelial Cells Express Cyclooxygenase-2 during Lipopolysaccharide-Induced Fever: Light and Electron Microscopic Immunocytochemical Studies
Open accessAbstract
Cyclooxygenase-2 (COX-2), a key enzyme in the biosynthesis of prostaglandins, is induced in brain blood vessels by pyrogens, and its essential role in fever has been hypothesized. In this study, we determined (1) the type of cells that express cyclooxygenase-2 in brain blood vessels of lipopolysaccharide-treated rats, and (2) the precise relationship between the time course of fever and that of cyclooxygenase-2 protein expression in these cells. Five hours after the lipopolysaccharide injection (100 microg/kg, i.p.), cyclooxygenase-2-like immunoreactive cells were found in the parenchymal and subarachnoidal blood vessels. In these blood vessels, the cyclooxygenase-2-like immunoreactivity was restricted to the perinuclear region of the endothelial cells as revealed by a laser confocal microscopy, double-immunofluorescence staining with an endothelial marker, and immunoelectron microscopy. On the other hand, the cyclooxygenase-2-like immunoreactive cells were distinct from microglia or perivascular/meningeal macrophages as revealed by double immunostaining with macrophage/microglia-specific antibodies. Cyclooxygenase-2-like immunoreactive cells were first found at 1.5 hr after the lipopolysaccharide injection, at which time the fever had not been developed. After that, the number of cyclooxygenase-2-like immunoreactive cells and fever followed a similar time course, both being highest at 5 hr after the lipopolysaccharide injection and both returning to the baseline by 24 hr. These results demonstrate that brain endothelial cells are the primary sites where the activation of arachidonic acid cascade takes place during fever after intraperitoneal injection of lipopolysaccharide.
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Activated vascular endothelial cells respond through the induction of COX-2 (and not COX-1) that produces PGE2, which in turn resets the thermostatic control to a higher temperature.
“These activated vascular endothelial cells respond through the induction of COX-2 (and not COX-1) that produces PGE 2 , which in turn resits the thermostatic control to a higher temperature [112,116,118].”
From Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action (2021) · cites this paper as [116]
The Abstract and the section “Timing of COX-2 expression and its physiological relevance” report COX-2 induction in brain endothelial cells during LPS-induced fever and propose that it promotes PGE2 production, which acts on CNS neurons to evoke fever. The paper treats endothelial PGE2 production as a hypothesis still requiring confirmation; it does not establish the claimed exclusion of COX-1 or describe a reset of thermostatic control. (LLM, conf=0.87)
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Cites
Synthesis of Antihemophilic Factor Antigen by Cultured Human Endothelial Cells
JAFFE, E. A., Hoyer, L. W., & Nachman, R. L. (1973) · Journal of Clinical Investigation · doi:10.1172/jci107471 · Cited by 1,262 · see citing works
Yamagata, K., Andreasson, K. I., Kaufmann, W. E., Barnes, C. A., & Worley, P. F. (1993) · Neuron · doi:10.1016/0896-6273(93)90192-t · Cited by 1,224 · see citing works
Fever: Role of Pyrogens and Cryogens
Kluger, M. J. (1991) · Physiological Reviews · doi:10.1152/physrev.1991.71.1.93 · Cited by 1,220 · see citing works
Herschman, H. R. (1996) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(95)00194-8 · Cited by 1,200 · see citing works
Sickness behavior as a new target for drug development
Kent, S., Bluthé, R.-M., Kelley, K. W., & Dantzer, R. (1992) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(92)90012-u · Cited by 863 · see citing works
A molecular basis for bidirectional communication between the immune and neuroendocrine systems.
Blalock, J. E. (1989) · Physiological Reviews · doi:10.1152/physrev.1989.69.1.1 · Cited by 847 · see citing works
Cytokine-to-brain communication: A review & analysis of alternative mechanisms
Watkins, L. R., Maier, S. F., & Goehler, L. E. (1995) · Life Sciences · doi:10.1016/0024-3205(95)02047-m · Cited by 597 · see citing works
Characterization of inducible cyclooxygenase in rat brain
Breder, C., Dewitt, D., & Kraig, R. (1995) · The Journal of comparative neurology · doi:10.1002/cne.903550208 · Cited by 550 · see citing works
New Concepts on the Pathogenesis of Fever
Dinarello, C. A., Cannon, J. G., & Wolff, S. M. (1988) · Clinical Infectious Diseases · doi:10.1093/clinids/10.1.168 · Cited by 365 · see citing works
Cunningham, E. T., Wada, E., Carter, D., Tracey, D. E., Battey, J., & Souza, E. B. D. (1992) · Journal of Neuroscience · doi:10.1523/jneurosci.12-03-01101.1992 · Cited by 334 · see citing works
Cao, C., Matsumura, K., Yamagata, K., & Watanabe, Y. (1996) · Brain Research · doi:10.1016/0006-8993(96)00575-6 · Cited by 308 · see citing works
Self-citationElmquist, J. K., Breder, C. D., Sherin, J. E., Scammell, T. E., Hickey, W. F., DeWitt, D. L., & Saper, C. B. (1997) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19970505)381:2 · Cited by 282 · see citing works
Ericsson, A. B., Arias, C., & Sawchenko, P. E. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-18-07166.1997 · Cited by 281 · see citing works
Tilders, F. J. H., DeRuk, R. H., Van Dam, A.-M., Vincent, V. A. M., Schotanus, K., & Persoons, J. H. A. (1994) · Psychoneuroendocrinology · doi:10.1016/0306-4530(94)90010-8 · Cited by 277 · see citing works
Cao, C., Matsumura, K., Yamagata, K., & Watanabe, Y. (1995) · Brain Research · doi:10.1016/0006-8993(95)00839-i · Cited by 252 · see citing works
Self-citationVentromedial Preoptic Prostaglandin E2 Activates Fever-Producing Autonomic Pathways
Scammell, T. E., Elmquist, J. K., Griffin, J. D., & Saper, C. B. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-19-06246.1996 · Cited by 249 · see citing works
Cao, C., Matsumura, K., Yamagata, K., & Watanabe, Y. (1997) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1997.272.6.r1712 · Cited by 203 · see citing works
Self-citationBreder, C. D., & Saper, C. B. (1996) · Brain Research · doi:10.1016/0006-8993(95)01474-8 · Cited by 198 · see citing works
Prostaglandin E as the neural mediator of the febrile response.
Stitt, J. T. (1986) · PubMed · Cited by 197 · see citing works
Localization of type I interleukin-1 receptor mRNA in the rat brain
Yabuuchi, K., Minami, M., Katsumata, S., & Satoh, M. (1994) · Molecular Brain Research · doi:10.1016/0169-328x(94)90180-5 · Cited by 186 · see citing works
Wagner, D., & Marder, V. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)32879-5 · Cited by 163 · see citing works
Fever: How May Circulating Pyrogens Signal the Brain?
Cm, B., & SEHIC, E. (1997) · Physiology · doi:10.1152/physiologyonline.1997.12.1.1 · Cited by 147 · see citing works
Regulation of prostaglandin endoperoxide synthase (cyclooxygenase) isozyme expression
Goppelt‐Struebe, M. (1995) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/0952-3278(95)90039-x · Cited by 134 · see citing works
Mapping of prostaglandin E2 binding sites in rat brain using quantitative autoradiography
Matsumura, K., Watanabe, Y., Imai-Matsumura, K., Connolly, M., Koyama, Y., Onoe, H., & Watanabe, Y. (1992) · Brain Research · doi:10.1016/0006-8993(92)90720-t · Cited by 128 · see citing works
Self-citationMatsumura, K., Watanabe, Y., Onoe, H., Watanabe, Y., & Hayaishi, O. (1990) · Brain Research · doi:10.1016/0006-8993(90)91808-t · Cited by 117 · see citing works
Self-citationvan Dam, A., Brouns, M. R., Man‐A‐Hing, W. K. H., & BERKENBOSCH, F. (1993) · Brain Research · doi:10.1016/0006-8993(93)90922-a · Cited by 103 · see citing works
A Novel Subtype of the Prostacyclin Receptor Expressed in the Central Nervous System
Takechi, H., Matsumura, K., Watanabe, Y., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.10.5901 · Cited by 95 · see citing works
Self-citationMatsumura, K., Watanabe, Y., Onoe, H., & Watanabe, Y. (1995) · Neuroscience · doi:10.1016/0306-4522(94)00505-y · Cited by 93 · see citing works
Self-citationProstaglandins in Fever and the Mode of Action of Antipyretic Drugs
Milton, A. S. (1982) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-68569-9_10 · Cited by 80 · see citing works
de Vries, H. E., Hoogendoorn, K. H., Dijk, J. V., Zijlstra, F. J., van Dam, A., Breimer, D. D., van Berkel, T. J. C., Boer, A. G. D., & Kuiper, J. (1995) · Journal of Neuroimmunology · doi:10.1016/0165-5728(95)00009-q · Cited by 67 · see citing works
Matsumura, K., Cao, C., Watanabe, Y., & Watanabe, Y. (1998) · Progress in brain research · doi:10.1016/s0079-6123(08)62040-3 · Cited by 47 · see citing works
Self-citationFluorescence Labeling of the Capillary Network in Rat Brains
Theilen, H., & Kuschinsky, W. (1992) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1992.47 · Cited by 27 · see citing works
Monocytic-endothelial cell interaction: regulation of prostanoid synthesis in human coculture
Koll, S., Goppelt‐Struebe, M., Hauser, I., et al. (1997) · Journal of Leukocyte Biology · doi:10.1002/jlb.61.6.679 · Cited by 12 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [31]31. Watkins LR, Maier SF, Goehler L E (1995) C ytokine-to-brain commu- nication: a review and analysis of alternative mechanisms. Life Sci 57:1011-1026.
Cited by
Sorted by citations
Central circuitries for body temperature regulation and fever
Nakamura, K. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00109.2011 · Cited by 543 · see citing works
Mechanism of Action of Acetaminophen: Is There a Cyclooxygenase 3?
Botting, R. M. (2000) · Clinical Infectious Diseases · doi:10.1086/317520 · Cited by 350 · see citing works
Neural circuitry engaged by prostaglandins during the sickness syndrome
Saper, C. B., Romanovsky, A. A., & Scammell, T. E. (2012) · Nature Neuroscience · doi:10.1038/nn.3159 · Cited by 285 · see citing works
Jaeger, L. B., Dohgu, S., Sultana, R., Lynch, J. L., Owen, J. B., Erickson, M. A., Shah, G. N., Price, T. O., Fleegal-Demotta, M. A., Butterfiled, D. A., et al. (2009) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2009.01.017 · Cited by 281 · see citing works
Li, S., Wang, Y., Matsumura, K., Ballou, L. R., Morham, S. G., & Blatteis, C. M. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01225-1 · Cited by 270 · see citing works
Self-citationDual Roles for Perivascular Macrophages in Immune-to-Brain Signaling
Serrats, J., Schiltz, J. C., García-Bueno, B., van Rooijen, N., Reyes, T. M., & Sawchenko, P. E. (2010) · Neuron · doi:10.1016/j.neuron.2009.11.032 · Cited by 253 · see citing works
Konsman, J. P., Luheshi, G. N., Bluthé, R., & Dantzer, R. (2000) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2000.01319.x · Cited by 234 · see citing works
Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action
Ayoub, S. S. (2021) · Temperature · doi:10.1080/23328940.2021.1886392 · Cited by 223 · see citing works
Gosselin, D., & Rivest, S. (2008) · Molecular Psychiatry · doi:10.1038/sj.mp.4002122 · Cited by 109 · see citing works
Turrin, N. P., & Rivest, S. (2004) · Experimental Biology and Medicine · doi:10.1177/153537020422901003 · Cited by 107 · see citing works
Cao, C., Matsumura, K., Ozaki, M., & Watanabe, Y. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-02-00716.1999 · Cited by 105 · see citing works
Self-citationAyoub, S. S., Botting, R. M., Goorha, S., Colville-Nash, P. R., Willoughby, D. A., & Ballou, L. R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404185101 · Cited by 104 · see citing works
Blais, V., Turrin, N. P., & Rivest, S. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03480.x · Cited by 72 · see citing works
Turnbull, A. V., Prehar, S., Kennedy, A. R., Little, R. A., & Hopkins, S. J. (2003) · Endocrinology · doi:10.1210/en.2002-220964 · Cited by 66 · see citing works
Acetaminophen: Antipyretic or hypothermic in mice? In either case, PGHS-1b (COX-3) is irrelevant
Li, S., Dou, W., Tang, Y., Goorha, S., Ballou, L. R., & Blatteis, C. M. (2008) · Prostaglandins & Other Lipid Mediators · doi:10.1016/j.prostaglandins.2007.10.007 · Cited by 63 · see citing works
Steiner, A. A., Li, S., Llanos-Q., J., & Blatteis, C. M. (2001) · Neuroimmunomodulation · doi:10.1159/000054289 · Cited by 50 · see citing works
Ayoub, S. S., & Flower, R. J. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172609 · Cited by 19 · see citing works
- Authors
- Matsumura, K., Cao, C., Ozaki, M., Morii, H., Nakadate, K., & Watanabe, Y.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1998-08-15
- Volume
- 18
- Issue
- 16
- Pages
- 6279-6289
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6793199
- OpenAlex
- W2168390615
- Cited by
- 247
- References
- 33
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 7 · 2019: 5 · 2018: 9 · 2017: 7 · 2016: 4 · 2015: 9 · 2014: 9 · 2013: 6 · 2012: 7
- FWCI
- 14.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Thermal Regulation in Medicine
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cyclooxygenase-2, brain endothelial cells, lipopolysaccharide, fever, prostaglandin synthesis, arachidonic acid metabolism, pyrogens, cerebral vasculature, immunoelectron microscopy, immunofluorescence
- MeSH terms
- Animals, Cerebrovascular Circulation, Endothelium, Vascular, Fever, Immunohistochemistry, Isoenzymes, Lipopolysaccharides, Male, Microscopy, Electron, Prostaglandin-Endoperoxide Synthases, Staining and Labeling, Time Factors, Blotting, Western, Rats, Wistar, Rats, Cyclooxygenase 2
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