Inflammation in Human Brain Injury: Intracerebral Concentrations of IL-1 α,IL-1 β,and Their Endogenous Inhibitor IL-1ra

Abstract

Following traumatic brain injury (TBI), cascades of inflammatory processes occur. Laboratory studies implicate the cytokines interleukin-1α (IL-1α) and IL-1β in the pathophysiology of TBI and cerebral ischemia, whilst exogenous and endogenous interleukin-1 receptor antagonist (IL-1ra) is neuroprotective. We analyzed IL-1α, IL-1β, and IL-1ra in brain microdialysates (100-kDa membrane) in 15 TBI patients. We also analyzed energy-related molecules (glucose, lactate, pyruvate, glutamate, and the lactate/pyruvate ratio) in these brain microdialysates. Mean of mean (± SD) in vitro microdialysis percentage recoveries (extraction efficiencies) were IL-1α 19.7 ± 7.6%, IL-1β 23.9 ± 10.5%, and IL-1ra 20.9 ± 6.3%. In the patients' brain microdialysates, mean of mean cytokine concentrations (not corrected for percentage recovery) were IL-1α 5.6 ± 14.8 pg/mL, IL-1β 10.4 ± 14.7 pg/mL, and IL-1ra 2796 ± 2918 pg/mL. IL-1ra was consistently much higher than IL-1α and IL-1β. There were no significant relationships between IL-1 family cytokines and energy-related molecules. There was a significant correlation between increasing IL-1β and increasing IL-1ra (Spearman r = 0.59, p = 0.028). There was also a significant relationship between increasing IL-1ra and decreasing intracranial pressure (Spearman r = −0.57, p = 0.041). High concentrations of IL-1ra, and also high IL-1ra/IL-1β ratio, were associated with better outcome (Mann Whitney, p = 0.018 and p = 0.0201, respectively), within these 15 patients. It is unclear whether these IL-1ra concentrations are sufficient to antagonize the effects of IL-1β in vivo. This study demonstrates feasibility of our microdialysis methodology in recovering IL-1 family cytokines for assessing their inter-relationships in the injured human brain, and suggests a neuroprotective role for IL-1ra. It remains to be seen whether exogenous IL-1ra or other agents can be used to manipulate cytokine levels in the brain, for potential therapeutic effect.