Increased interleukin-6 levels in cerebrospinal fluid following subarachnoid hemorrhage

Restricted access

✓ Serum and cerebrospinal fluid (CSF) samples from 12 patients were analyzed for interleukin (IL)-6, soluble IL-2 receptor (1L-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.

Article Information

Address reprint requests to: Tiit Mathiesen, M.D., Ph.D., Department of Neurosurgery, Karolinska Hospital, S-104 01 Stockholm, Sweden.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Graphs showing cerebrospinal fluid (CSF) (upper) and serum (lower) levels of interleukin (IL)-6 on Days 1, 3, 6, and 9 in 12 patients (pat's) with subarachnoid hemorrhage. Values below 67 pg/ml in CSF and 24 pg/ml in serum were regarded as normal. A marked increase in CSF IL-6 was detected, with a maximum value on Day 6. The high CSF levels were not paralleled by an increase in serum levels. The finding probably reflects a severe inflammatory involvement of the central nervous system. A separate analysis showed a statistically significant increase in only the subgroup of patients suffering a delayed ischemic neurological deficit.

  • View in gallery

    Graphs showing cerebrospinal fluid (CSF) (upper) and serum (lower) levels of soluble interleukin-2 receptor (sIL-2R) on Days 1, 3, 6, and 9 in 12 patients (pat's) with subarachnoid hemorrhage. Values below 20 U/ml in CSF and 970 U/ml in serum were regarded as normal. Moderately increased CSF sIL-2R values were detected in 11 of the 12 patients. The CSF values did not correlate with serum values, suggesting the presence of activated T cells in the central nervous system rather than passive transfer of sIL-2R across the blood-brain barrier.

  • View in gallery

    Graphs showing cerebrospinal fluid (CSF) (upper) and serum (lower) levels of soluble CD8 (sCD8) on Days 1, 3, 6, and 9 in 12 patients (pat's) with subarachnoid hemorrhage. Values below elevated 43 U/ml in CSF and 470 U/ml in serum were regarded as normal. Slightly elevated CSF sCD8 values in six patients may reflect the initial hemorrhage. The increase in serum sCD8 probably reflects a mild systemic activation of the suppressor/cytotoxic T-cell subpopulation.

References

1.

Aarden LADe Groot EFSchaap OLet al: Production of hybridoma growth factor by human monocytes. Eur J Immunol 17:141114161987Eur J Immunol 17:

2.

Boutin BMatsuguchi LLebon Pet al: Soluble IL-2 receptors in acute and subacute encephalitis. Ann Neurol 22:6586611987Ann Neurol 22:

3.

Butler LDLayman NKRiedl PEet al: Neuroendocrine regulation of in vivo cytokine production and effects: I. In vivo regulatory networks involving the neuroendocrine system, interleukin-1 and tumor necrosis factor-α. J Neuroimmunol 24:1431531989in vivo cytokine production and effects: I. In vivoJ Neuroimmunol 24:

4.

Dinarello CA: An update on human interleukin-1. J Clin Immunol 5:2872971985Dinarello CA: An update on human interleukin-1. J Clin Immunol 5:

5.

Freedman MSLoertscher RCashman NRet al: Immunoregulatory properties of T-cell lines derived from the systemic and intrathecal compartments: a phenotypic and functional study. Ann Neurol 27:2582651990Ann Neurol 27:

6.

Frei KLeist TPMeager Aet al: Production of B cell stimulatory factor-2 and interferon-gamma in the central nervous system during viral meningitis and encephalitis. Evaluation in a murine model infection and in patients. J Exp Med 168:4494531988J Exp Med 168:

7.

Frei KMalipiero UVLeist TPet al: On the cellular source and function of interleukin 6 produced in the central nervous system in viral disease. Eur J Immunol 19:6896941989Eur J Immunol 19:

8.

Frohman EMven der Noort SGupta S: Astrocytes and intracerebral immune responses. J Clin Immunol 9:191989J Clin Immunol 9:

9.

Giulian D: Ameboid microglia as effectors of inflammation in the central nervous system. J Neurosci Res 18:1551711987Giulian D: Ameboid microglia as effectors of inflammation in the central nervous system. J Neurosci Res 18:

10.

Griffin DEWard BJJauregui Eet al: Immune activation in measles. N Engl J Med 320:166716721989N Engl J Med 320:

11.

Heros RCZervas NTVarsos V: Cerebral vasospasm after subarachnoid hemorrhage: an update. Ann Neurol 14:5996081983Ann Neurol 14:

12.

Hirano TTaga TNakano Net al: Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFP-2). Proc Natl Acad Sci USA 82:549054941985Proc Natl Acad Sci USA 82:

13.

Jackson IJ: Aseptic hemogenic meningitis. An experimental study of aseptic meningeal reactions due to blood and its breakdown products. Arch Neurol Psychiatry 62:5725891949Jackson IJ: Aseptic hemogenic meningitis. An experimental study of aseptic meningeal reactions due to blood and its breakdown products. Arch Neurol Psychiatry 62:

14.

Kabiersch Adel Rey AHonegger CGet al: Interleukin-1 induces changes in norepinephrine metabolism in the rat brain. Brain Behav Immun 2:2672741988Brain Behav Immun 2:

15.

Kittur SDKittur DSSoncrant TTet al: Soluble interleukin-2 receptors in cerebrospinal fluid from individuals with various neurological disorders. Ann Neurol 28:1681731990Ann Neurol 28:

16.

Krueger JMDinarello CAShoham Set al: Interferon alpha-2 enhances slow-wave sleep in rabbits. Int J Immunopharmacol 9:23301987Int J Immunopharmacol 9:

17.

Leppert DFrei KGallo Pet al: Brain tumors: detection of B-cell stimulatory factor-2/interleukin-6 in the absence of oligoclonal bands of immunoglobulins. J Neuroimmunol 24:2592641989J Neuroimmunol 24:

18.

Mathiesen TFuchs DWachter Het al: Increased CSF neopterin levels in subarachnoid hemorrhage. J Neurosurg 73:69711990J Neurosurg 73:

19.

Matsui MMori KJSaida T: Cellular immunoregulatory mechanisms in the central nervous system: characterization of noninflammatory and inflammatory cerebrospinal fluid lymphocytes. Ann Neurol 27:6476511990Ann Neurol 27:

20.

Mayberg MROkada TBark DH: The role of hemoglobin in arterial narrowing after subarachnoid hemorrhage. J Neurosurg 72:6346401990J Neurosurg 72:

21.

Neil-Dwyer GCruickshank J: The blood leucocyte count and its prognostic significance in subarachnoid haemorrhage. Brain 97:79861974Brain 97:

22.

Okada MSakaguchi NYoshimura Net al: B cell growth factors and B cell differentiation factor from human T hybridomas. Two distinct kinds of B cell growth factors and their synergism in B cell proliferation. J Exp Med 157:5835901983J Exp Med 157:

23.

Østergaard JRKristensen Svehag SEet al: Immune complexes and complement activation following rupture of intracranial saccular aneurysms. J Neurosurg 66:8918971987J Neurosurg 66:

24.

Pellettieri LNilsson BCarlsson CAet al: Serum immunocomplexes in patients with subarachnoid hemorrhage. Neurosurgery 19:7677711986Neurosurgery 19:

25.

Peterson JWKwun BDHackett JDet al: The role of inflammation in experimental cerebral vasospasm. J Neurosurg 72:7677741990J Neurosurg 72:

26.

Peterson JWKwun BDTeramura Aet al: Immunological reaction against the aging human subarachnoid erythrocyte. A model for the onset of cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg 71:7187261989J Neurosurg 71:

27.

Weir BDisney LGrace Met al: Dazily trends in white blood cell count and temperature after subarachnoid hemorrhage from aneurysm. Neurosurgery 25:1611651989Neurosurgery 25:

28.

Weir BGrace MHansen Jet al: Time course of vasospasm in man. J Neurosurg 48:1731781978J Neurosurg 48:

29.

Woodroofe MNSarna GSWadhwa Met al: Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production. J Neuroimmunol 33:2272361991in vivo microdialysis: evidence of a role for microglia in cytokine production. J Neuroimmunol 33:

TrendMD

Cited By

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 14 14 10
Full Text Views 78 78 25
PDF Downloads 72 72 29
EPUB Downloads 0 0 0

PubMed

Google Scholar