Abstract
Tumor necrosis factor (TNF) and interleukin-(IL)-18 are important mediators of neuroinflammation after closed head injury (CHI). Both mediators have been previously found to be significantly elevated in the intracranial compartment after brain injury, both in patients as well as in experimental model systems. However, the interrelation and regulation of these crucial cytokines within the injured brain has not yet been investigated. The present study was designed to assess a potential regulation of intracranial IL-18 levels by TNF based on a clinical study in head-injured patients and an experimental model in mice. In the first part, we investigated the interrelationship between the daily TNF and IL-18 cerebrospinal fluid levels in 10 patients with severe CHI for up to 14 days after trauma. In the second part of the study, the potential TNF-dependent regulation of intracerebral IL-18 levels was further characterized in an experimental set-up in mice: (1) in a standardized model of CHI in TNF/lymphotoxin-α gene-deficient mice and wild-type (WT) littermates, and (2) by intracerebro-ventricular injection of mouse recombinant TNF in WT C57BL/6 mice. The results demonstrate an inverse correlation of intrathecal TNF and IL-18 levels in head-injured patients and a TNF-dependent inhibition of IL-18 after intracerebral injection in mice. These findings imply a potential new anti-inflammatory mechanism of TNF by attenuation of IL-18, thus confirming the proposed "dual" function of this cytokine in the pathophysiology of traumatic brain injury.
Highlights
The neuropathological sequelae of brain injury are mediated in large part by a profound host-mediated intracranial inflammatory response [3,4,5]
The pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin (IL)-18 have been identified as crucial mediators of neuroinflammation after brain injury [6,7,8,9]
This notion has been supported by experimental studies in rodents which demonstrated neuroprotective effects by pharmacological inhibition of either TNF or IL-18 after closed head injury (CHI) [9,10,11]
Summary
We sought to determine the interrelationship between intracranial TNF and IL-18 levels in a clinical study on patients with severe CHI and in an experimental model in mice. In the clinical part of the study on CHI patients, the mean IL-18 concentrations in ventricular CSF collected up to 14 days after trauma were significantly higher than in control lumbar CSF from patients undergoing diagnostic spinal tap (P< 0.05, repeated measures ANOVA; Table 1).
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