title: Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra.
abstract: Following traumatic brain injury (TBI), cascades of inflammatory processes occur. Laboratory studies implicate the cytokines interleukin-1alpha (IL-1alpha) and IL-1beta in the pathophysiology of TBI and cerebral ischemia, whilst exogenous and endogenous interleukin-1 receptor antagonist (IL-1ra) is neuroprotective. We analyzed IL-1alpha, IL-1beta, 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-1alpha 19.7+/-7.6%, IL-1beta 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-1alpha 5.6+/-14.8 pg/mL, IL-1beta 10.4+/-14.7 pg/mL, and IL-1ra 2796+/-2918 pg/mL. IL-1ra was consistently much higher than IL-1alpha and IL-1beta. There were no significant relationships between IL-1 family cytokines and energy-related molecules. There was a significant correlation between increasing IL-1beta 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-1beta 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-1beta 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.
authors.affiliation: Academic Unit of Neurosurgery, Department of Clinical Neurosciences, Wolfson Brain Imaging Centre, University of Cambridge, and Addenbrooke's Hospital, Cambridge, United Kingdom. pjah2@cam.ac.uk
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hutchinson
authors.forename: Mark T
authors.initials: MT
authors.lastname: O'Connell
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Rothwell
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Hopkins
authors.forename: Jürgens
authors.initials: J
authors.lastname: Nortje
authors.forename: Keri L H
authors.initials: KL
authors.lastname: Carpenter
authors.forename: Ivan
authors.initials: I
authors.lastname: Timofeev
authors.forename: Pippa G
authors.initials: PG
authors.lastname: Al-Rawi
authors.forename: David K
authors.initials: DK
authors.lastname: Menon
authors.forename: John D
authors.initials: JD
authors.lastname: Pickard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001923:Brain Chemistry / Q000502:physiology*; D001930:Brain Injuries / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000032:analysis* / Q000378:metabolism; D053582:Interleukin-1alpha / Q000032:analysis* / Q000378:metabolism; D053583:Interleukin-1beta / Q000032:analysis* / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008875:Middle Aged
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D053583:Interleukin-1beta