Cerebrospinal Fluid Interleukin-6 Levels Research Articles

INTRATHECAL AND SERUM INTERLEUKIN-6 AND THE ACUTE-PHASE RESPONSE IN PATIENTS WITH SEVERE TRAUMATIC BRAIN INJURIES

Patients with severe traumatic brain injury (TBI) show a profound acute-phase response. Because interleukin-6 (IL-6) is an important mediator of these pathophysiological changes, IL-6 levels were monitored in the cerebrospinal fluid (CSF) and serum of 20 patients with severe isolated TBI. All patients received indwelling ventricular catheters for intracranial pressure monitoring and for release of CSF when intracranial pressure exceeded 15 mmHg. CSF and blood samples were drawn daily for up to 14 days. The CSF/serum albumin ratio (QA) served as a parameter of blood brain barrier dysfunction. Differential blood counts as well as the acute-phase proteins C-reactive protein, alpha 1-antitrypsin, and fibrinogen were recorded. IL-6 was detected in all CSF samples and reached values of up to 31,000 pg/mL, while serum levels remained significantly lower (alpha < or = .01) and never exceeded 1,100 pg/mL the entire study period. A correlation between CSF and serum IL-6 was found initially after the trauma and corresponded to a severe dysfunction of the blood brain barrier (r = .637, p = .001). Maximum IL-6 concentrations in serum correlated with peak levels of acute-phase proteins (C-reactive protein, alpha 1-antitrypsin, and fibrinogen). With regard to blood cell count, an initial leukocytosis combined with a borderline lymphocytopenia was observed. Thrombocytes decreased to a subnormal level during the first few days, but reached supranormal numbers by the end of the study period. Our results show that the increase of IL-6 levels in CSF and serum is followed by a profound acute-phase response in patients with TBI. Because cytokine concentrations are significantly lower in serum compared with CSF, we hypothesize that IL-6 produced in the central nervous system may play a role in initiating the acute-phase response.

Early intrathecal production of interleukin-6 predicts the size of brain lesion in stroke.

We have previously demonstrated that stroke influences systemic immune responses. The aim of the present study was to investigate patterns of local inflammatory response as a consequence of acute stroke. Thirty stroke patients were studied prospectively on days 0 to 3, 7 to 9, 21 to 26, and after day 90 with clinical evaluations, radiological assessments, and analysis of serum and cerebrospinal fluid cytokine levels. Significantly increased levels of interleukin-6 (IL-6) in cerebrospinal fluid (P < .001) were observed in virtually all patients studied compared with healthy control subjects. This increase was observed during the whole observation period but was significantly more pronounced within the first days after stroke onset, with a peak level on days 2 and 3. This initial increase was significantly correlated (r = .65, P = .002) with the volume of infarct measured by MRI 2 to 3 months later. Serum levels of IL-6 in stroke patients were significantly lower than cerebrospinal fluid levels of IL-6 (P = .013) and did not display any significant correlation to the size of the brain lesion. Also, increase in intrathecal but not systemic production of IL-1 beta was observed early during the stroke. Only minor increases of cerebrospinal fluid interferon-gamma levels were observed in two patients. Our study demonstrates an intrathecal production of IL-6 and IL-1 beta in patients with stroke, supporting the notion of localized inflammatory response to acute brain lesion. In addition, the significant correlation between early intrathecal production of IL-6 and the subsequent size of the brain lesion can be used as a prognostic tool, predicting the size of the brain damage before it is possible to accurately visualize it with radiological methods.

Cytokine elevations in infants with bacterial and aseptic meningitis

We sought to determine whether the detection of cytokines, produced during the inflammatory response, would aid in the diagnosis of meningitis in young infants. We measured cerebrospinal fluid (CSF) and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) in 62 infants less than 6 months of age whose condition was evaluated for meningitis. Twenty infants had culture-proved meningitis, 22 had aseptic meningitis, and 20 control infants had no evidence of meningitis. The CSF IL-6 levels were elevated in all 20 infants with bacterial meningitis and in 9 of 22 infants with aseptic meningitis but were undetectable in all control subjects. Furthermore, CSF IL-6 levels were 10 times greater in infants with bacterial versus aseptic meningitis (p <0.001). Levels of TNF in CSF were detected in 12 of 20 infants with bacterial meningitis and were undetectable in infants with aseptic meningitis and in control infants (p <0.02). Plasma IL-6 and TNF levels were unreliable for the detection of meningitis in this patient population. We conclude that the presence of IL-6 in the CSF reliably identifies infants with meningitis and that the presence of CSF TNF is a highly specific indicator of bacterial meningeal inflammation. (J PEDIATR 1995;126:872-6)

Interleukin-6 levels in the cerebrospinal fluid and serum of patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy

Clinical and experimental findings suggest that humoral factors, such as anti-peripheral nerve antibodies and cytokines, may be implicated in the immunopathogenesis of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Interleukin-6 (IL-6) is a multifunctional cytokine that promotes immunoglobulin synthesis by B lymphocytes. Increased IL-6 release is associated with autoantibody production in a number of immune-mediated and neoplastic disorders. To investigate the possible involvement of abnormal IL-6 release in inflammatory polyneuropathies, we assayed IL-6 levels in the cerebrospinal fluid (CSF) and serum of 23 patients with acute GBS and seven with CIDP. We also studied 69 patients with other non-inflammatory neurological diseases (NIND), 25 with other inflammatory neurological diseases (IND), four with brain tumors (BT), and 15 normal donors (serum alone) as controls. We found detectable levels of IL-6 in the CSF of 57% of GBS, 43% of CIDP, 60% of IND, 75% of BT, and 4% of NIND. In GBS patients, no correlation was found between CSF IL-6 values and other laboratory or clinical parameters, such as CSF total protein, CSF albumin, CSF IgG, CSF/serum albumin ratio, functional disability score, and time elapsed from disease onset. Serum IL-6 levels were increased in six of 23 (26%) GBS, in one of 39 (3%) NIND, and in one of seven (14%) IND, but in none of the CIDP or BT patients. There was no correlation between serum and CSF IL-6 values, but cytokine levels in GBS sera correlated with time elapsed from clinical onset. In addition, we measured anti-GM1 IgG and IgM levels in the CSF and sera of GBS and CIDP patients to study the possible association of these autoantibodies with increased IL-6 secretion. In both CSF and sera of GBS or CIDP patients, increased anti-GM1 antibody levels were not associated with elevated IL-6. We conclude that elevated IL-6 levels are frequently detected in the CSF of patients with inflammatory polyneuropathies, especially GBS. The presence of a heightened IL-6 release, however, is not required for the production of anti-GM1 antibodies in GBS and CIDP patients. Additional studies may clarify whether testing CSF IL-6 levels in the early phase of GBS would help in defining the inflammatory nature of the polyneuropathy, prompting a faster choice of plasma exchange treatment.

Increased interleukin-6 levels in cerebrospinal fluid following subarachnoid hemorrhage.

Serum and cerebrospinal fluid (CSF) samples from 12 patients were analyzed for interleukin (IL)-6, soluble IL-2 receptor (IL-2R), and soluble CD8 levels in order to determine the immune activation profile following subarachnoid hemorrhage (SAH). Dramatically increased levels of IL-6 and moderate increases of soluble IL-2R were detected in the CSF in 11 of the 12 patients; slightly elevated levels of soluble CD8 were observed in six patients. The IL-6 levels were higher on Day 6 than on Days 3 and 9. The increases in IL-6, soluble IL-2R, and soluble CD8 levels in the CSF samples were not paralleled by increased values in the serum samples, and thus probably reflected an intrathecal synthesis of the cytokine. Passive transfer of IL-6 across the blood-brain barrier seemed not to occur since the serum and CSF levels of IL-6 showed a negative correlation. The findings suggest a severe inflammatory affection of the central nervous system that could be of importance in understanding the clinical course in patients following SAH.

Amyotrophic Lateral Sclerosis: Interleukin-6 Levels in Cerebrospinal Fluid

Recent observations indicate that antibodies to gangliosides are found in many patients with amyotrophic lateral sclerosis (ALS). If antigen-antibody complexes occur in ALS, elevations of cytokine levels might be expected, among them the cytokine interleukin-6 (IL-6). IL-6 is secreted by activated monocytes and other cell types and is an important mediator of the inflammatory response. We have measured cerebrospinal fluid (CSF) IL-6 levels in patients with ALS and compared them with those in psychiatric and neurodegenerative disorders not believed to be due to immune disorders of the central nervous system. We found no significant differences in CSF IL-6 levels between these groups.

Cerebrospinal fluid levels of IL-6 in patients with acute infections of the central nervous system.

Interleukin-6 (IL-6) activity was measured in the cerebrospinal fluid (CSF) of patients with acute bacterial or viral meningitis and in AIDS patients with various cerebral disorders. Increased levels of IL-6 were detected in the CSF of patients with bacterial meningitis. On the contrary, most of the samples from patients with viral meningitis (predominantly caused by mumps virus) had no detectable IL-6 activity in CSF. A moderate increase of IL-6 levels was detected in the CSF of AIDS patients with AIDS dementia complex (ADC), progressive multifocal leukoencephalopathy and cerebral toxoplasmosis. Moreover, higher levels of IL-6 were detected in the CSF of patients with cryptococcal meningitis. We conclude that the initial events of CSF inflammation in patients with acute viral meningitis are different from those in patients with acute bacterial meningitis, and the role of IL-6 is less critical to the process.

Cerebrospinal fluid interleukin-6 activity in HIV infection and inflammatory and noninflammatory diseases of the nervous system

Interleukin-6 (IL-6) activity was measured in the cerebrospinal fluid (CSF) of patients at different stages of human immunodeficiency (HIV) virus infection and of patients with multiple sclerosis (MS) or other inflammatory (OID) and noninflammatory neurological diseases (OND). In the advanced stages of HIV infection and in OID, IL-6 was detected more frequently (80 and 75% of the cases) and at higher concentrations than in the early stages of HIV infection, MS and OND (44, 48, and 44% of cases). Analysis of CSF and paired sera indicated that IL-6 production can be compartmentalized to either of the fluids. Evidence that altered blood-brain barrier functions can, at least in part, influence the CSF IL-6 levels was found in OID patients. No association was evident between intrathecal immunoglobulin synthesis and CSF IL-6 levels. Interleukin-1 (IL-1) levels were detectable in a minority of the samples from neurological patients; one OID patient had high levels of both CSF IL-1 and IL-6.