Cerebrospinal fluid interleukin 6 in amyotrophic lateral sclerosis: immunological parameter and comparison with inflammatory and non-inflammatory central nervous system diseases

https://doi.org/10.1016/S0022-510X(97)00228-1Get rights and content

Abstract

We assayed IL-6 in 105 cerebrospinal fluid (CSF) samples from patients with ALS, MS, HTLV-1 associated myelopathy (HAM), and controls. There was considerable overlap in IL-6 levels in all patient groups. The mean IL-6 in 27 patients with ALS was significantly higher than in 21 patients in the other neurological disease (OND) group (P=0.0075). There were no significant differences in MS or HAM and the OND control group. Overall, CSF IL-6 correlated with protein concentration but not with percentage IgG or IgG-albumin index. Patients with CSF oligoclonal bands were no more likely to have detectable IL-6 than patients without oligoclonal bands. Similarly, IL-6 did not correlate with clinical disease activity in MS when subgroups of patients were compared or when an individual patient was followed over time. The elevated IL-6 in ALS may reflect an ongoing humoral immune response, or IL-6 may be non-specifically expressed in these patients as a putative neurotrophic factor in response to nerve cell degeneration.

Introduction

IL-6 is a B cell differentiation factor that was first described by Hirano et al. (1985). Although usually T-cell derived, it can be produced by other cells including astrocytes and microglia in the central nervous system (CNS) (Benveniste et al., 1990, Frei et al., 1989, Woodroofe et al., 1991). Cerebrospinal fluid (CSF) levels of IL-6 are consistently elevated in herpes simplex virus encephalitis and other bacterial and viral CNS infections (Houssiau et al., 1988, Frei et al., 1988). In contrast, variable results have been reported in non-infectious CNS inflammatory diseases. IL-6 was detected in experimental allergic encephalomyelitis CSF (Gijbels et al., 1990) and systemic lupus erythematosus with central nervous system involvement (Hirohata and Miyamoto, 1990), but IL-6 was not detected in multiple sclerosis (MS) (Houssiau et al., 1988, Frei et al., 1988, Araga et al., 1991) (or detected no more frequently than in neurological disease controls) (Hauser et al., 1990). Reports of IL-6 in non-inflammatory CNS disease prompted the present study of CSF in patients with amyotrophic lateral sclerosis (ALS). We found a higher frequency of detection and higher levels of IL-6 in ALS than in the other neurological disease control group. In contrast, there was no significant difference in CSF IL-6 in either MS or HAM patients compared to other neurological disease controls, and there was no correlation of CSF immune parameters and IL-6 levels. These results are consistent with the hypothesis that CSF IL-6 in ALS has an non-immune origin, occurring as a neurotrophic response to nerve cell damage.

Section snippets

Patients

Diagnostic criteria used were for ALS (Mulder, 1982) MS (Poser et al., 1983) and HAM (Osame et al., 1987). All 19 ALS patients from Japan had progressive weakness without significant sensory disturbance, upper or lower motor neuron signs, muscle atrophy with fasciculation, and a neurogenic pattern on electromyography. Eight CSF ALS samples and two non-neurological disease controls were obtained from the National Neurological Research Bank (VA Wadsworth Medical Center, Los Angeles, CA). All HAM

Results

Table 1 shows CSF of patients in the ALS, MS, HAM, and OND groups. A mild pleocytosis was present in the MS and HAM groups and the protein was mildly elevated in the MS group. The highest mean values of both total IgG and percent IgG were in the HAM group.

As shown in Fig. 1, there was considerable overlap in IL-6 levels in all patient groups. A Kruskal-Wallis test comparing the five groups (3 experimental and 2 controls) was significant overall (P=0.0012).

Table 2 shows IL-6 detection in 78% of

Discussion

We found a modest, but statistically significant elevation of CSF IL-6 in ALS patients (Fig. 1). A published study using this same assay technique found no difference between 15 ALS patient and 20 controls with psychiatric or neurodegenerative disease (Krieger et al., 1992). In comparing these studies, a similar percentage of ALS patients had undetectable CSF IL-6 (6/27 versus 2/15); but 37% of our patients had IL-6 levels greater than 10 pg/ml compared to only 7% in the published study. The

References (25)

  • S.L. Hauser et al.

    Cytokine accumulations in CSF of multiple sclerosis patients: frequent detection of interleukin-1 and tumor necrosis factor but not interleukin-6

    Neurology

    (1990)
  • T. Hirano et al.

    Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or B S Fp-2)

    Proc. Natl. Acad. Sci. USA

    (1985)
  • Cited by (139)

    • The IL-1 family cytokines and receptors in autoimmune diseases

      2020, Autoimmunity Reviews
      Citation Excerpt :

      Several studies have suggested that immune activation and inflammatory mechanisms play an active role in ALS pathogenesis [154]. Infiltrating macrophages and T cells, with increased levels of IL-6, have been reported in both CSF [155] and sera [156] of ALS patients, as well as increased circulating levels of TNF-α and its soluble receptors [157]. Abundant evidence indicates the involvement of IL-1F cytokines in ALS.

    • Interleukin-6 and amyotrophic lateral sclerosis

      2019, Journal of the Neurological Sciences
      Citation Excerpt :

      Interleukin-6 (IL-6) is multifunctional cytokine involved in the regulation of the immune response, inflammation, metabolism and hematopoiesis, produced by immune and blood cells, endothelial cells, and myocytes on contraction [1], which can cross the blood-brain barrier [2] and has been extensively investigated in neurodegenerative disorders. A number of previous studies have reported increased serum and CSF levels of IL-6 in patients with ALS, probably related to the well-described role of inflammatory processes in motor neuron degeneration [3–7]. Studies of skin biopsies in ALS patients have demonstrated higher IL-6 immunoreactivity as compared with diseased control subjects.

    View all citing articles on Scopus
    View full text