Brain-IL-1 beta triggers astrogliosis through induction of IL-6: inhibition by propranolol and IL-10.

BACKGROUND: Gliosis is a characteristic pathology in many central nervous system (CNS) diseases. Cytokines are considered to be effectors of gliosis. It has been shown that pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6 boost glia scar formation. On the other hand, anti-inflammatory cytokines, such as IL-10 and IL-1 receptor antagonist (ra), can act neuroprotectively. Furthermore, various immune mediators and neurotransmitters can modulate the onset of gliosis. MATERIAL/METHODS: We used 100 male Sprague-Dawley rats to investigate the mechanisms of brain-cytokine-induced astrogliosis using an in vivo model of convection-enhanced delivery of cytokines (IL-beta, IL-6, tumor necrosis factor (TNF)-alpha) into the cerebro-ventricular system. The protective effects of the anti-inflammatory cytokine IL-10 and the neurotransmitter propranolol were also investigated. RESULTS: With this paradigm, we could clearly demonstrate that IL-6 is a key cytokine mediating astrogliosis, noticeable in the increased expression of glial fibrillary acidic protein (GFAP). Thus intra-cerebroventricular infusion of IL-6 increased GFAP expression in a dose-dependent manner. Furthermore, GFAP expression was also increased by IL-beta, which correspondingly triggered an IL-6 release into the CSF. Accordingly, TNF-alpha, which did not induce IL-6 release, also did not induce gliosis. On the other hand, substances which decrease IL-beta-induced IL-6 production, such as propranolol and IL-10, also dramatically decreased IL-beta triggered gliosis. CONCLUSIONS: IL-6 infusion, as well as IL-beta-induced IL-6 release into the CSF, increase GFAP expression in the cerebral cortex and hippocampus. Accordingly, blockade of the IL-beta-induced IL-6 release by IL-10 and propranolol decreases GFAP expression.

Norepinephrine infusion increases interleukin-6 in plasma and cerebrospinal fluid of brain-injured rats.

BACKGROUND: Significantly increased plasma and CSF IL-6 levels reflect underlying tissue damage following clinical and experimental traumatic brain injury (TBI). Catecholamines, used under clinical conditions to maintain adequate cerebral perfusion pressure, induce a sustained IL-6 release. Thus an additional elevation in IL-6 could aggravate brain edema in the acute posttraumatic phase. We studied the changes in plasma and cerebrospinal fluid (CSF) IL-6 levels 4 and 24 hours after experimental TBI and assessed possible time-dependent effects of norepinephrine infusion on IL-6 and brain edema. MATERIAL/METHODS: Paired plasma and CSF IL-6 measured at 4 and 24 hours following TBI (n=10) were compared to levels in non-traumatized rats (n=5). In a placebo-controlled trial, 20 brain-injured male Sprague-Dawley rats were randomized to receive norepinephrine or NaCl for 90 minutes at 4 or 24 hours after TBI. Plasma IL-6 was measured before, during, and after the infusion period. One hour after stopping the infusion, CSF IL-6 and hemispheric swelling were determined. RESULTS: During the first posttraumatic day, plasma and CSF IL-6 levels were significantly increased compared to non-traumatized rats, reaching the highest values at 24 hours (p<0.05). Norepinephrine infusion significantly increased plasma IL-6 at 7 and 27 hours after TBI; IL-6 was significantly elevated in CSF only at 7 hours (p<0.05). Brain edema was not aggravated. CONCLUSIONS: The norepinephrine-induced increase in plasma and CSF IL-6 suggests that concomitant norepinephrine administration needs to be considered when interpreting systemic and local changes in IL-6 levels in TBI patients.

Early IL-6 plasma concentrations correlate with severity of brain injury and pneumonia in brain-injured patients.

BACKGROUND: Brain injury as well as early inflammatory and endocrine responses were found to be indicators for infectious complications in patients with multiple injuries. In this context, brain-derived inflammatory response as well as centrally triggered neuroendocrine activation and systemic immunodepression seem to be of major importance. Therefore, we hypothesize that a circulating index of inflammatory or endocrine function measured soon after brain injury (in patients with admission Glasgow Coma Scale [GCS] score of 4-7) would discriminate severe from moderate injury as indexed by GCS status on postinjury day 7. METHODS: In a retrospective study, 25 patients with either acute traumatic brain injury or cerebral hemorrhage and an initial GCS score of 4 to 7 were examined. Blood samples were obtained at different time points, and different immune variables and neuroendocrine hormones were determined. According to the GCS score on day 7, patients were divided into two groups (GCS score > or = 8, moderate brain injury; and GCS score < 8, severe brain injury or patients who died within the first week) for comparison of variables. Concluding from the results of this retrospective analysis, in a prospective study patients (n = 26) were divided into two groups according to their interleukin (IL)-6 plasma concentrations on day 1 (IL-6 > or = 100 pg/mL and IL 6 < 100 pg/mL). After 7 days, the GCS score, the infection rate, and the mortality were compared between these two groups. RESULTS: In the retrospective study, we could show that severe brain injury (as assessed by GCS score and mortality on day 7) was associated with high plasma levels of pro- and anti-inflammatory cytokines, acute phase proteins, and neuroendocrine hormones within 2 to 6 hours after the acute event. Among the investigated variables, elevated IL-6 plasma concentrations were stable up to 1 day after the acute event with a high predictive value with regard to the short-term prognosis and incidence of infectious complications within the first week. Because of this stability during the first 24 hours, we selected IL-6 for further studies. In the prospective study with a calculated cut-off IL-6 plasma concentration of 100 pg/mL on day 1, the predictive value of this parameter regarding the severity of the brain injury was fully confirmed (positive predictive value, 0.94; this value represents the observed pretest probability of 0.62). All patients who died (n = 5) or developed infectious complications within the first week (n = 8) showed plasma IL-6 levels > or = 100 pg/mL on day 1. CONCLUSION: The IL-6 plasma level 1 day after the acute event with a cut-off of 100 pg/mL (Immulite) seems to be a predictor for short-term prognosis and infectious complications in brain-injured patients.