Induction of pro-inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat
Abstract
Although it is generally accepted that pro-inflammatory cytokines produced by cells of the central nervous system play important roles in the communication between the central nervous system and the immune system during sepsis, it is not clear whether these cytokines are produced in the brain under subseptic conditions. In this study, we used in situ hybridization to examine the mRNA expression of the pro-inflammatory cytokines IL-1beta and TNFalpha in the brains of rats 2 and 12 h after they were challenged by peripheral injections of lipopolysaccharide (LPS) ranging from 0.01 to 1000 microg/kg. Unlike septic doses of LPS (> 500 microg/kg), which induce global expression of pro-inflammatory cytokines in the brain, subseptic doses of LPS (0.01-10 microg/kg) induced IL-1beta and TNFalpha mRNA expression only in the choroid plexus, the circumventricular organs, and meninges. The expression of the cytokine-responsive immediate early gene I kappaB alpha was induced in the brain after doses of LPS as low as 0.1 microg/kg. I kappaB alpha mRNA expression was confined to sites where IL-1beta and TNFalpha were expressed. These results indicate that the induction and action of pro-inflammatory cytokines during subseptic infection occur at the blood-brain barrier and at circumventricular organs, which may be sites for elaboration of signal molecules that communicate peripheral immune status to the brain.
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Pathways and mechanisms for cytokine signaling of the central nervous system.
Licinio, J., & Wong, M. L. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119846 · Cited by 220 · see citing works
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From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395 · see citing works
Cytokines and their relationship to the symptoms and outcome of cancer
Seruga, B., Zhang, H., Bernstein, L. J., & Tannock, I. F. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2507 · Cited by 652 · see citing works
The impact of microglial activation on blood-brain barrier in brain diseases
da Fonseca, A. C. C., Matias, D., Garcia, C., Amaral, R., Geraldo, L. H., Freitas, C., & Lima, F. R. S. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00362 · Cited by 572 · see citing works
The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders
Knezevic, E., Nenic, K., Milanovic, V., & Knezevic, N. N. (2023) · Cells · doi:10.3390/cells12232726 · Cited by 564 · see citing works
“IL-1 beta promotes proinflammatory genes and proteins in the brain [106–108], as well as IL-1 beta-induced sickness behavior in rodents, resulting in social withdrawal, loss of appetite, decreased motor activity, and a decrease in cognitive function [109] (see Table 1).”
BackgroundThe role of inflammation and the gut microbiome in depression and anxiety
Peirce, J. M., & Alviña, K. (2019) · Journal of Neuroscience Research · doi:10.1002/jnr.24476 · Cited by 466 · see citing works
Urakubo, A., Jarskog, L. F., Lieberman, J. A., & Gilmore, J. H. (2001) · Schizophrenia Research · doi:10.1016/s0920-9964(00)00032-3 · Cited by 405 · see citing works
Chakravarty, S., & Herkenham, M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4268-04.2005 · Cited by 396 · see citing works
Self-citationImmune and neuroendocrine mechanisms of stress vulnerability and resilience
Ménard, C., Pfau, M. L., Hodes, G. E., & Russo, S. J. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.90 · Cited by 374 · see citing works
Review: Systemic inflammation and<scp>A</scp>lzheimer's disease
Holmes, C. (2013) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2012.01307.x · Cited by 356 · see citing works
The Neuropathology of Septic Shock
Sharshar, T., Annane, D., de la Gradmaison, G. L., Brouland, J. P., Hopkinson, N. S., & Gray, F. (2004) · Brain Pathology · doi:10.1111/j.1750-3639.2004.tb00494.x · Cited by 348 · see citing works
Choroid Plexus in the Central Nervous System: Biology and Physiopathology
Strazielle, N., & Ghersi-Egea, J.-F. (2000) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/59.7.561 · Cited by 307 · see citing works
Molecular links between endocrine, nervous and immune system during chronic stress
Zefferino, R., Di Gioia, S., & Conese, M. (2021) · Brain and Behavior · doi:10.1002/brb3.1960 · Cited by 204 · see citing works
How and why do T cells and their derived cytokines affect the injured and healthy brain?
Filiano, A. J., Gadani, S. P., & Kipnis, J. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.39 · Cited by 199 · see citing works
Raison, C. L., Borisov, A. S., Woolwine, B. J., Massung, B., Vogt, G., & Miller, A. H. (2010) · Molecular Psychiatry · doi:10.1038/mp.2008.58 · Cited by 183 · see citing works
Doyle, H. H., Eidson, L. N., Sinkiewicz, D. M., & Murphy, A. Z. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2906-16.2017 · Cited by 166 · see citing works
The choroid plexus—a multi-role player during infectious diseases of the CNS
Schwerk, C., Tenenbaum, T., Kim, K. S., & Schroten, H. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00080 · Cited by 147 · see citing works
Hypothalamic inflammation and energy homeostasis: Resolving the paradox
Thaler, J. P., Choi, S. J., Schwartz, M. W., & Wisse, B. E. (2010) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.10.002 · Cited by 144 · see citing works
Streit (2005) · doi:10.1179/016164105x49463 · Cited by 100 · see citing works
Visceral Inflammation and Immune Activation Stress the Brain
Holzer, P., Farzi, A., Hassan, A. M., Zenz, G., Jačan, A., & Reichmann, F. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01613 · Cited by 84 · see citing works
Lawson, M. A., McCusker, R. H., & Kelley, K. W. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-54 · Cited by 80 · see citing works
Jenkins, T. A., Harte, M. K., Stenson, G., & Reynolds, G. P. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.07.014 · Cited by 61 · see citing works
- Authors
- Quan, N., Stern, E. L., Whiteside, M. B., & Herkenham, M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Quan, Ning
- Venue
- Journal of Neuroimmunology
- Publisher
- Elsevier BV
- Published
- 1999-01
- Volume
- 93
- Issue
- 1-2
- Pages
- 72-80
- ISSN
- 0165-5728 (ISSN-L)
- OpenAlex
- W2063026836
- Cited by
- 251
- References
- 1
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 8 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 10 · 2019: 10 · 2018: 11 · 2017: 7 · 2016: 7 · 2015: 7 · 2014: 13 · 2013: 12 · 2012: 6
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroimmunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- inflammatory cytokines, IL-1β, TNF-α, lipopolysaccharide, choroid plexus, circumventricular organs, meninges, IκBα, blood-brain barrier, neuroimmune interactions, sepsis
- MeSH terms
- Animals, Autoradiography, Brain, Encephalitis, Injections, Intravenous, Interleukin-1, Lipopolysaccharides, Male, Paraventricular Hypothalamic Nucleus, RNA, Messenger, Subfornical Organ, Tumor Necrosis Factor-alpha, Gene Expression Regulation, Enzymologic, Proto-Oncogene Proteins c-fos, Rats, Sprague-Dawley, Receptors, Interleukin-1, Solitary Nucleus, Caspase 1, Rats
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