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Brain interleukin-1? and the intrinsic receptor antagonist control peripheral Toll-like receptor 3-mediated suppression of spontaneous activity in rats.

ABSTRACT: During acute viral infections such as influenza, humans often experience not only transient fever, but also prolonged fatigue or depressive feelings with a decrease in social activity for days or weeks. These feelings are thought to be due to neuroinflammation in the brain. Recent studies have suggested that chronic neuroinflammation is a precipitating event of various neurological disorders, but the mechanism determining the duration of neuroinflammation has not been elucidated. In this study, neuroinflammation was induced by intraperitoneal injection of polyriboinosinic:polyribocytidylic acid (poly I:C), a Toll-like receptor-3 agonist that mimics viral infection in male Sprague-Dawley rats, and then investigated how the neuroinflammation shift from acute to the chronic state. The rats showed transient fever and prolonged suppression of spontaneous activity for several days following poly I:C injection. NS-398, a cyclooxygenase-2 inhibitor, completely prevented fever, but did not improve spontaneous activity, indicating that suppression of spontaneous activity was not induced by the arachidonate cascade that generated the fever. The animals overexpressed interleukin (IL)-1? and IL-1 receptor antagonist (IL-1ra) in the brain including the cerebral cortex. Blocking the IL-1 receptor in the brain by intracerebroventricular (i.c.v.) infusion of recombinant IL-1ra completely blocked the poly I:C-induced suppression of spontaneous activity and attenuated amplification of brain interferon (IFN)-? expression, which has been reported to produce fatigue-like behavior by suppressing the serotonergic system. Furthermore, i.c.v. infusion of neutralizing antibody for IL-1ra prolonged recovery from suppression of spontaneous activity. Our findings indicated that IL-1? is the key trigger of neuroinflammation and that IL-1ra prevents the neuroinflammation entering the chronic state.

SUBMITTER: Yamato M

PROVIDER: S-EPMC3951245 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Brain interleukin-1β and the intrinsic receptor antagonist control peripheral Toll-like receptor 3-mediated suppression of spontaneous activity in rats.

Yamato Masanori M Tamura Yasuhisa Y Eguchi Asami A Kume Satoshi S Miyashige Yukiharu Y Nakano Masayuki M Watanabe Yasuyoshi Y Kataoka Yosky Y

PloS one 20140312 3

During acute viral infections such as influenza, humans often experience not only transient fever, but also prolonged fatigue or depressive feelings with a decrease in social activity for days or weeks. These feelings are thought to be due to neuroinflammation in the brain. Recent studies have suggested that chronic neuroinflammation is a precipitating event of various neurological disorders, but the mechanism determining the duration of neuroinflammation has not been elucidated. In this study, ...[more]

PMID: 24621600

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Project description:Objectivesβ-cell dysfunction and apoptosis associated with islet inflammation play a key role in the pathogenesis of type 2 diabetes (T2D). Growing evidence suggests that islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to islet inflammation and β-cell death in T2D. We recently showed the role of interleukin-1β (IL-1β)/Fas/caspase-8 apoptotic pathway in amyloid-induced β-cell death. In this study, we used human islets in culture as an ex vivo model of amyloid formation to: (1) investigate the effects of amyloid on islet levels of the natural IL-1 receptor antagonist (IL-1Ra); (2) examine if modulating the IL-1β/IL-1Ra balance can prevent amyloid-induced β-cell Fas upregulation and apoptosis.MethodsIsolated human islets (n = 10 donors) were cultured in elevated glucose (to form amyloid) with or without a neutralizing human IL-1β antibody for up to 7 days. Parallel studies were performed with human islets in which amyloid formation was prevented by adeno-siRNA-mediated suppression of hIAPP expression (as control). β-cell levels of IL-1Ra, Fas, apoptosis as well as islet function, insulin- and amyloid-positive areas, and IL-1Ra release were assessed.ResultsProgressive amyloid formation in human islets during culture was associated with alterations in IL-1Ra. Islet IL-1Ra levels were higher at early stages but were markedly reduced at later stages of amyloid formation. Furthermore, IL-1Ra release from human islets was reduced during 7-day culture in a time-dependent manner. These changes in IL-1Ra production and release from human islets during amyloid formation adversely correlated with islet IL-1β levels, β-cell Fas expression and apoptosis. Treatment with IL-1β neutralizing antibody markedly reduced amyloid-induced β-cell Fas expression and apoptosis, thereby improving islet β-cell survival and function during culture.ConclusionsThese data suggest that amyloid formation impairs the balance between IL-1β and IL-1Ra in islets by increasing IL-1β production and reducing IL-1Ra levels thereby promoting β-cell dysfunction and death. Restoring the IL-1β/IL-1Ra ratio may provide an effective strategy to protect islet β-cells from amyloid toxicity in T2D.

Project description:OBJECTIVE:Plasma interleukin-1 beta may influence sepsis mortality, yet recombinant human interleukin-1 receptor antagonist did not reduce mortality in randomized trials. We tested for heterogeneity in the treatment effect of recombinant human interleukin-1 receptor antagonist by baseline plasma interleukin-1 beta or interleukin-1 receptor antagonist concentration. DESIGN:Retrospective subgroup analysis of randomized controlled trial. SETTING:Multicenter North American and European clinical trial. PATIENTS:Five hundred twenty-nine subjects with sepsis and hypotension or hypoperfusion, representing 59% of the original trial population. INTERVENTIONS:Random assignment of placebo or recombinant human interleukin-1 receptor antagonist × 72 hours. MEASUREMENTS AND MAIN RESULTS:We measured prerandomization plasma interleukin-1 beta and interleukin-1 receptor antagonist and tested for statistical interaction between recombinant human interleukin-1 receptor antagonist treatment and baseline plasma interleukin-1 receptor antagonist or interleukin-1 beta concentration on 28-day mortality. There was significant heterogeneity in the effect of recombinant human interleukin-1 receptor antagonist treatment by plasma interleukin-1 receptor antagonist concentration whether plasma interleukin-1 receptor antagonist was divided into deciles (interaction p = 0.046) or dichotomized (interaction p = 0.028). Interaction remained present across different predicted mortality levels. Among subjects with baseline plasma interleukin-1 receptor antagonist above 2,071 pg/mL (n = 283), recombinant human interleukin-1 receptor antagonist therapy reduced adjusted mortality from 45.4% to 34.3% (adjusted risk difference, -0.12; 95% CI, -0.23 to -0.01), p = 0.044. Mortality in subjects with plasma interleukin-1 receptor antagonist below 2,071 pg/mL was not reduced by recombinant human interleukin-1 receptor antagonist (adjusted risk difference, +0.07; 95% CI, -0.04 to +0.17), p = 0.230. Interaction between plasma interleukin-1 beta concentration and recombinant human interleukin-1 receptor antagonist treatment was not statistically significant. CONCLUSIONS:We report a heterogeneous effect of recombinant human interleukin-1 receptor antagonist on 28-day sepsis mortality that is potentially predictable by plasma interleukin-1 receptor antagonist in one trial. A precision clinical trial of recombinant human interleukin-1 receptor antagonist targeted to septic patients with high plasma interleukin-1 receptor antagonist may be worthy of consideration.

Dataset Information

Brain interleukin-1? and the intrinsic receptor antagonist control peripheral Toll-like receptor 3-mediated suppression of spontaneous activity in rats.

Publications

Brain interleukin-1β and the intrinsic receptor antagonist control peripheral Toll-like receptor 3-mediated suppression of spontaneous activity in rats.

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