Role of endogenous interleukin‐1 receptor antagonist in regulating fever induced by localised inflammation in the rat
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1. Interleukin (IL)-1 is a mediator of host defence responses to inflammation and injury, including fever, but its sites of synthesis and action have not been fully elucidated. The actions of IL-1 are antagonised by IL-1 receptor antagonist (IL-1ra). The present study tested the hypothesis that IL-1 and IL-1ra are produced locally at sites of peripheral inflammation in rats, and that endogenous IL-1ra acts to limit the fever resulting from the inflammation. 2. Injection of lipopolysaccharide (LPS; 100 microg kg-1) into a subcutaneous air pouch (I.PO.) of rats induced a significant increase in body temperature. Virtually all (approximately 85 %) of the injected LPS was recovered from the pouch between 1 and 8 h (when the experiment was terminated) after injection of LPS, but LPS was undetectable (< 50 pg ml-1) in plasma at any time. Concentrations of immunoreactive IL-1alpha and IL-1beta were increased significantly in the pouch at 1, 2, 3, 5 and 8 h after injection of LPS, corresponding with the rise in body temperature and the fever peak. The appearance of IL-1ra was delayed until 2 h. Thereafter, the concentrations of IL-1beta and IL-1ra increased in parallel with the development of fever, while the concentrations of IL-1alpha remained constant. IL-1ra, but not IL-1alpha or IL-1bet, was detected in significant quantities in the plasma of LPS-injected animals. 3. Treatment of rats with an anti-IL-1ra serum (2 ml, I.PO.) at the time of injection of LPS (10 or 100 microg kg-1, I.PO.) abolished the appearance of IL-1ra in the circulation. Although neutralisation of endogenous IL-1ra did not affect the maximum body temperature reached after injection of submaximum (10 microg kg-1, I.PO.) or maximum (100 microg kg-1, I.PO.) doses of LPS, the duration of the fever was significantly prolonged, and was associated with a 3- to 4-fold increase in immunoreactive IL-1beta concentrations in the pouch fluid, but not in the plasma, at the 8 h time point. 4. These data show that effects of local (I.PO.) injection of LPS are not due to its action in the circulation or at distant sites (such as at the blood-brain barrier). These data also show that locally produced IL-1ra, in response to injection (I.PO.) of LPS, inhibits the production and/or action of locally produced IL-1beta. The ability of IL-1ra to limit the duration, rather than the magnitude of the fever, is consistent with its delayed production, relative to IL-IL-1ra, therefore, appears to play a key role in the resolution of fever induced by localised inflammatory responses.
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IL-1ra plays a key role in local inflammatory processes and is more sensitive than other cytokines such as IL-1β to peripheral changes in the blood.
“In fact, IL-1ra appears to play a key role in local inflammatory processes37 and has been shown to be more sensitive than other cytokines such as IL-1β to peripheral changes in the blood compared to alterations of specific local tissues concentrations38.”
From Increased core body temperature in astronauts during long-duration space missions (2017) · cites this paper as [38]
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Increased core body temperature in astronauts during long-duration space missions
Stahn, A. C., Werner, A., Opatz, O., Maggioni, M. A., Steinach, M., von Ahlefeld, V. W., Moore, A., Crucian, B. E., Smith, S. M., Zwart, S. R., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-15560-w · Cited by 100 · see citing works
- Authors
- Cartmell, T., Luheshi, G. N., Hopkins, S. J., Rothwell, N. J., & Poole, S.
- Affiliations
- University of Manchester (GB)
- Salford Royal Hospital (GB)
- National Institute for Biological Standards and Control (GB)
- Corresponding author
- Cartmell, T.
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2001-02
- Volume
- 531
- Issue
- 1
- Pages
- 171-180
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC2278459
- OpenAlex
- W2070839349
- Cited by
- 62
- References
- 60
- Citations by year
- 2024: 1 · 2023: 2 · 2019: 1 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 5 · 2013: 4 · 2012: 2
- FWCI
- 4.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Topics
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Thermal Regulation in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- interleukin-1 receptor antagonist, interleukin-1, fever, lipopolysaccharide, air pouch, IL-1β, IL-1α, fever duration, host defense, subcutaneous injection, rat model
- MeSH terms
- Animals, Biological Assay, Body Temperature, Enzyme-Linked Immunosorbent Assay, Fever, Horseshoe Crabs, Inflammation, Interleukin-1, Lipopolysaccharides, Cytokines, Rats, Sprague-Dawley, Receptors, Interleukin-1, Rats
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