• Proc. Natl. Acad. Sci. U.S.A. · Jul 2012

    Comparative Study Clinical Trial

    Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice.

    • Jon Lampa, Marie Westman, Diana Kadetoff, Anna Nordenstedt Agréus, Erwan Le Maître, Caroline Gillis-Haegerstrand, Magnus Andersson, Mohsen Khademi, Maripat Corr, Christina A Christianson, Ada Delaney, Tony L Yaksh, Eva Kosek, and Camilla I Svensson.
    • Unit of Rheumatology, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, SE-171 77 Stockholm, Sweden. jon.lampa@ki.se
    • Proc. Natl. Acad. Sci. U.S.A. 2012 Jul 31;109(31):12728-33.

    AbstractDuring 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.

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