Raised parenchymal interleukin-6 levels correlate with improved outcome after traumatic brain injury

Abstract

Previous studies have suggested that an increased production of the pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) can influence patient outcome following a severe head injury. However, these studies have relied upon measurements of cytokine levels in CSF or serum, rather than the brain parenchyma itself. Recently, a method of intracranial microdialysis has been developed which permits the efficient recovery of macromolecules from the parenchyma. We have used this technique to investigate whether there is a correlation between patient outcome and parenchymally derived cytokines. Fourteen patients who were admitted to the Wessex Neurological Centre with severe head injury were selected for the study. This group of patients consisted of seven males and seven females with an age range of 21-77 years. Patients were treated according to standard protocols including emergency craniotomy where necessary. Microdialysis probes were implanted into the frontal region contralateral to the site of the primary injury. Approximately 200 micro l of dialysate was recovered every 8-12 h, and the concentrations of IL-6, IL-1beta and nerve growth factor (NGF) were determined by commercial enzyme-linked immunosorbent assays. Patients were assessed initially using the Glasgow coma score, and survivors were assessed after 6 months using the Glasgow outcome scale. Significantly (P = 0.04) higher levels of IL-6 were found in patients who survived compared with those who died. Also, there was a significant correlation between peak IL-6 levels and Glasgow outcome scores (r(2) = 0.34, P = 0.03, n = 14). The levels of IL-1beta and NGF were similar in both groups of patients. From these data, we suggest that IL-6 is an endogenous neuroprotective cytokine produced in response to severe head trauma.

Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: analysis from a randomized placebo-controlled Phase II clinical trial

“…1,2,6,8,9,[11][12][13]30,32 Similar to TNF-a, it is detectable by 1 hour postinjury and peaks in brain parenchyma at approximately 2-8 hours. 32 However, unlike TNF-a, particularly related to the DAI model, IL-6 levels do not depend on the injury model, and this is a more sensitive marker.…”

“…Similarly, the role of proinflammatory (interleukin [IL]-6, IL-1, tumor necrosis factor-a [TNF-a]) and antiinflammatory (IL-4, IL-10, transforming growth factor) cytokines has been validated in recent trials. 1,2,6,8,9,[11][12][13]22,26,27,30,36 More recently, posttraumatic suppression of the hypothalamic-pituitary-adrenal axis and an increase in cytokine-mediated peripheral aromatase activity, leading to an imbalance in sex steroid (estrogen [Eg], progesterone [Pg], and testosterone) serum levels, have been areas of active interest for precise understanding of the mechanisms involved. 5,15,23,25,29 Most of the recent literature deals with these biomarkers in isolation, and there is a paucity of existing literature for establishing a comprehensive model dealing with all 3 domains together.…”

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

“…57 An in vivo microdialysis study has shown that increased parenchymal IL-6 levels correlate with survival and GOS suggesting that IL-6 is an endogenous neuroprotective cytokine. 58 Furthermore, increased CSF levels of IL-6 have been reported to correlate with improved outcome in pediatric TBI. 59 Interestingly, induced hypothermia has no effect on IL-6 levels in children, a finding that is in contrast to that observed in adult TBI patients in which IL-6 levels were found to decrease after therapeutic hypothermia.…”

Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells

“…The highly developed endothelial cell-cell (EC-EC) contacts of the BBB restrict paracellular diffusion, forcing most solute flux across the cerebral endothelium to occur by transcellular routes (Banks, 1999;Miller, 2010). Dysfunction of the BBB, and thus BBB hyperpermeability, has been implicated in the onset and/or progression of several neuroinflammatory diseases, such as traumatic brain injury, stroke, multiple sclerosis, encephalitis and Alzheimer disease (Hawkins and Davis, 2005;Winter et al, 2004;Zlokovic, 2008). Hence, understanding the mechanisms of inflammatory-mediated BBB disruption is of crucial importance.…”