Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice
Edited by Dennis A. Carson, University of California at San Diego, La Jolla, CA, and approved June 25, 2012 (received for review November 17, 2011)
Abstract
During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.
Acknowledgments
We thank Rosmarie Johnson and Seija Johansson for excellent assistance in clinical assessments and lumbar puncture. We also thank Tomas Hökfelt for critical reading of the manuscript. This work was supported by grants from the National Institute of Health, the Swedish Research Council, the Swedish Rheumatism Association, the Swedish Foundation for Strategic Research, the Arthritis Foundation, and King Gustaf V’s 80-Year Foundation.
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Published online: July 16, 2012
Published in issue: July 31, 2012
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Acknowledgments
We thank Rosmarie Johnson and Seija Johansson for excellent assistance in clinical assessments and lumbar puncture. We also thank Tomas Hökfelt for critical reading of the manuscript. This work was supported by grants from the National Institute of Health, the Swedish Research Council, the Swedish Rheumatism Association, the Swedish Foundation for Strategic Research, the Arthritis Foundation, and King Gustaf V’s 80-Year Foundation.
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This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice, Proc. Natl. Acad. Sci. U.S.A.
109 (31) 12728-12733,
https://doi.org/10.1073/pnas.1118748109
(2012).
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