Elsevier

Journal of Neuroimmunology

Volume 101, Issue 2, 15 November 1999, Pages 211-221
Journal of Neuroimmunology

IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-α, TGF-β1 and blood–brain barrier function

https://doi.org/10.1016/S0165-5728(99)00148-4Get rights and content

Abstract

Controlling the extent of inflammatory responses following brain injury may be beneficial since posttraumatic intracranial inflammation has been associated with adverse outcome. In order to elucidate the potential role of anti-inflammatory mediators, the production of interleukin-10 (IL-10) was monitored in paired cerebrospinal fluid (CSF) and serum of 28 patients with severe traumatic brain injury (TBI) and compared to control samples. The pattern of IL-10 was analyzed with respect to the patterns of IL-6, tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) in both fluids during a time period of up to 22 days. In parallel, the function/dysfunction of the blood–brain barrier (BBB) was monitored using the CSF-/serum-albumin quotient (QA) and compared to intrathecal cytokine levels. Mean IL-10 concentration in CSF was elevated in 26 out of 28 TBI patients (range: 1.3–41.7 pg/ml) compared to controls (cut-off: 1.06 pg/ml), whereas only seven patients had elevated mean IL-10 concentration in serum (range: 5.4–23 pg/ml; cut-off: 5.14 pg/ml). The time course of IL-10 was similar in both fluids, showing a peak during the first days and a second, lower rise in the second week. Intrathecal IL-10 synthesis is hypothesized since CSF-IL-10 levels exceeded serum-IL-10 levels in most of the patients, IL-10-index (CSF/serum-IL-10/QA) was elevated in 23 individuals, and elevation of CSF-IL-10 showed to be independent from severe BBB dysfunction. Neither CSF nor serum IL-10 values correlated with the dysfunction of the BBB. IL-10, IL-6 and TGF-β1 showed similar patterns in CSF over time, whereas rises of TNF-α corresponded to declines of IL-10 levels. Our results suggest that IL-10 is predominantly induced intrathecally after severe TBI where it may downregulate inflammatory events following traumatic brain damage.

Introduction

Traumatic brain injury (TBI) is one of the major causes of morbidity and mortality in young patients (Marshall et al., 1991; Gennarelli, 1993; Jennett, 1993). The initial injury is often aggravated by secondary insults which occur with a considerable delay from the initial traumatic impact (Povlishock and Christman, 1995). The posttraumatic inflammatory response within the intrathecal compartment is believed to be one of the causes contributing to tissue damage as well as to the induction of neuroreparative mechanisms (Benveniste et al., 1995; Balasingam and Yong, 1996; Heesen et al., 1996; Kossmann et al., 1996, Kossmann et al., 1997). The anti-inflammatory cytokine interleukin-10 (IL-10) has the capacity to suppress several inflammatory events such as production of interferon-γ (IFN-γ), IL-1, IL-6 and tumor necrosis factor-α (TNF-α) by macrophages and lymphocytes, upregulation of MHC class II antigens as well as T cell proliferation (for review: de Waal Malefyt et al., 1991). In addition, IL-10 inhibits the adhesion of leukocytes to the endothelium and the production of reactive oxygen intermediates and nitric oxide by macrophages (Cunha et al., 1992; Krakauer, 1995). The intrathecal expression and release of proinflammatory cytokines following severe TBI has been described in humans as well as in experimental models (Ott et al., 1994; Shohami et al., 1994; Morganti-Kossmann and Kossmann, 1995; Bell et al., 1997; Morganti-Kossmann et al., 1997, Morganti-Kossmann et al., 1999; Hans et al., 1999). Unstimulated cultured microglia produce IL-10 and transforming growth factor-β1 (TGF-β1) rather than proinflammatory mediators which are promptly induced after challenge with lipopolysaccharide (LPS) and accompanied by a reduction of anti-inflammatory cytokines (Xiao et al., 1996). Human astrocytes and brain endothelial cells do not seem to produce IL-10 after in vitro stimulation with LPS. However, once exposed to IL-10 in culture, they release nerve growth factor (NGF) which supports neuronal survival and differentiation (Corsini et al., 1996).

In neuropathology, IL-10 was detected in cerebrospinal fluid (CSF) of adults with bacterial and viral meningitis, HIV-related encephalitis, and encephalomalacial sarcoidosis (Gallo et al., 1994; van Furth et al., 1995). In experimental listerial meningitis, IL-10 was shown to suppress macrophage bactericidal activity and also MHC class II expression on stimulated cultured microglial cells (Frei et al., 1993, Frei et al., 1994). The beneficial activity of IL-10 in pneumococcal meningitis was shown following systemic, but not intrathecal IL-10 administration resulting in attenuated cerebral blood flow elevation, intracranial pressure, edema, and CSF white blood cell count in pneumococcal meningitis (Koedel et al., 1996). Production of IL-10 was also demonstrated in experimental allergic encephalomyelitis (EAE) and corresponded to a reduction of proinflammatory cytokine mRNA expression in the spinal cord (Kennedy et al., 1992). Improved neurological recovery following fluid percussion injury in the rat was also demonstrated when IL-10 was administered intravenously and subcutaneously, but not intraventricularly. In these animals, treatment with IL-10 resulted in reduction of TNF-α and IL-1 cerebral expression (Knoblach and Faden, 1998).

IL-10 has recently been shown to be increased in CSF within the first 3 days after severe TBI in children and its levels were found associated with increased age and mortality (Bell et al., 1997). The present study was therefore undertaken to determine the levels of IL-10 in adults following severe TBI for a longer time period and to investigate its relationship to the dysfunction of the BBB and to the release of the proinflammatory cytokines IL-6, TNF-α and the suppressive mediator TGF-β1.

This is the first study to show IL-10 levels in CSF as well as in paired serum samples over a time period of up to 22 days after TBI. The immunosuppressive function of IL-10 may be of fundamental importance in downregulating the inflammatory response after TBI, possibly contributing to reduce the onset of secondary brain damage.

Section snippets

Patients and sample collection

After admission to the Division of Trauma Surgery, University Hospital Zürich, Switzerland, a total of 28 patients, 21 male, 7 female, age 36±16 years (mean±SD, range 16–67) with severe isolated TBI were included in this study. All patients presented with a Glasgow Coma Score (GCS)≤8 (Teasdale and Jennett, 1974) upon admission and alterations in the computed tomography (CT) of the brain. Intracranial hematomas were surgically removed if necessary. Intraventricular catheters were placed in all

IL-10 levels in CSF and serum of patients with severe traumatic brain injury

IL-10 was measured in paired CSF and serum samples of 28 TBI patients for a maximum of 22 days posttrauma. Elevated IL-10 CSF levels were found in 26 out of 28 patients with TBI, and the mean of all IL-10 concentrations of the single patient measured during the whole study period was above control levels in 15 patients (range of maximal values: 1.8–440.3 pg/ml; range of means: 1.3–41.7 pg/ml; cut-off limit: 1.06 pg/ml; Table 2; Fig. 1A). Seventeen patients showed their maximal CSF-IL-10

Discussion

In the present study, we have identified the anti-inflammatory cytokine IL-10 in the CSF and in serum of patients suffering from severe TBI. The measurements performed for an extensive time period allowed us to define the pattern of this cytokine in both fluids and to determine whether or not intrathecal synthesis may occur. The hypothesis of an intrathecal IL-10 production is supported by the following observations. First, the presence of CSF-IL-10 levels greater than serum levels was detected

Acknowledgements

The excellent technical assistance of Emerita Ammann is acknowledged. We thank Dr. Reto Stocker for helpful discussion and critical review of the manuscript. This study was supported by the Swiss National Science Foundation grant numbers 31.36375.92 and 31.42490.94.

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