Following traumatic brain injury (TBI), cascades of inflammatory processes occur. Laboratory studies implicate the cytokines interleukin-1α(IL-1α) and IL-1βin 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 lactatepyruvate ratio) in these brain microdialysates. Mean of mean (± SD) in vitromicrodialysis percentage recoveries (extraction efficiencies) were IL-1α19.7 ± 7.6, IL-1β23.9 ± 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-1α5.6 ± 14.8 pgmL, IL-1β10.4 ± 14.7 pgmL, and IL-1ra 2796 ± 2918 pgmL. IL-1ra was consistently much higher than IL-1αand IL-1β. There were no significant relationships between IL-1 family cytokines and energy-related molecules. There was a significant correlation between increasing IL-1βand 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-1raIL-1βratio, 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-1βin 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. [ABSTRACT FROM AUTHOR]