Inflammation in Human Brain Injury: Intracerebral Concentrations of IL-1α, IL-1β, 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.

The Cytokine Response to Human Traumatic Brain Injury: Temporal Profiles and Evidence for Cerebral Parenchymal Production

“…The magnitude of these peaks (at least twice the median value) suggests that these are biologically relevant changes that reflect the underlying pathophysiology. For this reason, we did not exclude the data from our earliest samples as has been suggested previously (Hutchinson et al, 2007;Mellergard et al, 2008). Second, the temporal profile of a number of cytokines shows no peaks at all.…”

Pulmonary Complications in Patients with Brain Injury

“…), [14][15][16][17][18] used. 3,10 All of this increases lung capillary permeability and results in bilateral pulmonary infiltrates that lead to severe hypoxemia with a low PaO 2 /FiO 2 ratio (<300 mm Hg in ALI, <200 mm Hg in ARDS) and decreased lung compliance.…”

Effects of Therapeutic Hypothermia on Inflammasome Signaling after Traumatic Brain Injury

“…Increased production of cytokines of the interleukin-1 (IL-1) family, such as IL-1b, is well documented, providing clear evidence for a pivotal role of this cytokine in triggering TBI-induced inflammatory process (Ciallella et al, 2002;Hutchinson et al, 2007;Kinoshita et al, 2002;Knoblach and Faden, 2000;Shohami et al, 1994). These cellular and molecular changes represent therapeutic targets for reducing the devastating consequences of TBI.…”