Cerebrospinal fluid interleukin-1 receptor antagonist and tumor necrosis factor—α following subarachnoid hemorrhage

Restricted access

✓ Subarachnoid hemorrhage (SAH) causes an inflammatory reaction and may lead to ischemic brain damage. Experimental ischemia has been shown to be connected with the alarm-reaction cytokines interleukin-1 receptor antagonist (IL-1Ra) and tumor necrosis factor—α (TNFα). Increased levels of these cytokines, however, have not been detected thus far in patients following an SAH event.

For this reason daily cerebrospinal fluid (CSF) samples were collected from 22 consecutively enrolled patients with SAH and from 10 non-SAH patients (controls). The CSF samples were studied using immunoassays for IL-1Ra and TNFα to investigate whether an SAH caused increased cytokine levels.

The mean IL-1Ra levels were significantly higher in patients with SAH who were in poor clinical condition on admission than in those who were in good condition (318 pg/ml vs. 82 pg/ml, p < 0.02). The IL-1Ra levels increased during delayed ischemic episodes and after surgery in patients who were in poor clinical condition. Significant increases in IL-1Ra and TNFα were detected during Days 4 through 10 in patients suffering from SAH who eventually had a poor outcome (p < 0.05). Patients with good outcomes and control patients had low levels of these cytokines.

The levels of IL-1Ra increased after surgery in patients with Hunt and Hess Grades III through V, but not in those with Grade I or II. This finding indicates that patients in poor clinical condition have a labile biochemical state in the brain that is reflected in increased cytokine levels following the surgical trauma.

Both IL-1Ra and TNFα are known to induce fever, malaise, leukocytosis, and nitric oxide synthesis and to mediate ischemic and traumatic brain injuries. The present study shows that levels of these cytokines increase after SAH occurs and that high cytokine levels correlate with brain damage. It is therefore likely that fever, leukocytosis, and nitric oxide synthesis are also mediated by IL-1 in patients suffering from SAH and it is probable that the inflammatory mediators contribute to brain damage.

Article Information

Address reprint requests to: Tiit Mathiesen, M.D., Ph.D., Department of Neurosurgery, Karolinska Hospital, S-171 76 Stockholm, Sweden.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Graph displaying the relationship between mean IL-1Ra levels (pg/ml) in patients with favorable (IL-1Ra F; GOS score of 4 or 5) and unfavorable (IL-1Ra U; GOS score of 1–3) outcomes on post-SAH Days 1 to 12. Mean IL-1Ra levels increased in patients with unfavorable outcomes, particularly between Days 4 and 11.

  • View in gallery

    Graph displaying the relationship between mean TNFα levels (pg/ml) in patients with favorable (TNF F; GOS score of 4 or 5) and unfavorable (TNF U; GOS score of 1–3) outcomes on post SAH Days 1 to 12. The mean TNFα levels increased in patients with unfavorable outcomes, particularly between Days 4 and 10.

  • View in gallery

    Graph showing IL-1Ra levels (pg/ml) on the 2 days before (ISCH −2 and ISCH −1), the day of (ISCH 0), and the day after (ISC +1) the onset of DID. The IL-1Ra levels rose significantly on the day of DID in all three patients with this diagnosis.

  • View in gallery

    Graph showing the mean IL-1Ra and TNFα levels before and after surgery for patients who underwent aneurysm clipping. Patients were divided into groups: those in good clinical condition (Hunt and Hess Grades I and II) and those in poor clinical condition (Hunt and Hess Grades III–V). The IL-1Ra levels increased significantly in patients who underwent surgery despite being in poor condition, but not in those in good condition. The TNFα levels were unaffected by surgery.

References

1.

Beamer NBCoull BMClark WMet al: Interleukin-6 and interleukin-1 receptor antagonist in acute stroke. Ann Neurol 37:8008041995Beamer NB Coull BM Clark WM et al: Interleukin-6 and interleukin-1 receptor antagonist in acute stroke. Ann Neurol 37:800–804 1995

2.

Borgerding RAMurphy S: Expression of inducible nitric oxide synthase in cerebral endothelial cells is regulated by cytokine-activated astrocytes. J Neurochem 65:134213471995Borgerding RA Murphy S: Expression of inducible nitric oxide synthase in cerebral endothelial cells is regulated by cytokine-activated astrocytes. J Neurochem 65:1342–1347 1995

3.

Bourdiol FToulmond SSerrano Aet al: Increase in W3 (peripheral type benzodiazepine) binding sites in the rat cortex and striatum after local injection of interleukin-1, tumor necrosis factor-α and lipopolysaccharide. Brain Res 543:1942001991Bourdiol F Toulmond S Serrano A et al: Increase in W3 (peripheral type benzodiazepine) binding sites in the rat cortex and striatum after local injection of interleukin-1 tumor necrosis factor-α and lipopolysaccharide. Brain Res 543:194–200 1991

4.

Buttini MAppel KSauter Aet al: Expression of tumor necrosis factor alpha after focal cerebral ischaemia in the rat. Neuroscience 71:1161996Buttini M Appel K Sauter A et al: Expression of tumor necrosis factor alpha after focal cerebral ischaemia in the rat. Neuroscience 71:1–16 1996

5.

Buttini MBoddeke HWHM: Peripheral lipopolysaccharide stimulation induces interleukin-1β messenger RNA in rat brain microglial cells. Neuroscience 65:5235301995Buttini M Boddeke HWHM: Peripheral lipopolysaccharide stimulation induces interleukin-1β messenger RNA in rat brain microglial cells. Neuroscience 65:523–530 1995

6.

Dinarello CA: Modalities for reducing interleukin 1 activity in disease. Immunol Today 14:2602641993Dinarello CA: Modalities for reducing interleukin 1 activity in disease. Immunol Today 14:260–264 1993

7.

Dinarello CA: An update on human interleukin 1: from molecular biology to clinical relevance. J Clin Immunol 5:2872971989Dinarello CA: An update on human interleukin 1: from molecular biology to clinical relevance. J Clin Immunol 5:287–297 1989

8.

Ecker ARiemenschneider PA: Arteriographic demonstration of spasm of the intracranial arteries. With special reference to saccular arterial aneurysms. J Neurosurg 8:6606671951Ecker A Riemenschneider PA: Arteriographic demonstration of spasm of the intracranial arteries. With special reference to saccular arterial aneurysms. J Neurosurg 8:660–667 1951

9.

Engervall PAndersson BBjörkholm M: Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia. Br J Haematol 91:8388451995Engervall P Andersson B Björkholm M: Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia. Br J Haematol 91:838–845 1995

10.

Feuerstein GZLiu TBarone FC: Cytokines, inflammation, and brain injury: role of tumor necrosis factor-alpha. Cerebrovasc Brain Metab Rev 6:3413601994Feuerstein GZ Liu T Barone FC: Cytokines inflammation and brain injury: role of tumor necrosis factor-alpha. Cerebrovasc Brain Metab Rev 6:341–360 1994

11.

Findlay JMMacdonald RLWeir BKA: Current concepts of pathophysiology and management of cerebral vasospasm following aneurysmal SAH. Cerebrovasc Brain Metab Rev 3:3363611991Findlay JM Macdonald RL Weir BKA: Current concepts of pathophysiology and management of cerebral vasospasm following aneurysmal SAH. Cerebrovasc Brain Metab Rev 3:336–361 1991

12.

Fisher MPlante GMDoyle EM: Inhibition of inflammatory cell-mediated myelin oxidation and interleukin-1 beta generation by a 21-aminosteroid, U74500A. J Neurol Sci 119:1891941993Fisher M Plante GM Doyle EM: Inhibition of inflammatory cell-mediated myelin oxidation and interleukin-1 beta generation by a 21-aminosteroid U74500A. J Neurol Sci 119:189–194 1993

13.

Giulian DCorpuz MChapman Set al: Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system. J Neurosci Res 36:6816931993Giulian D Corpuz M Chapman S et al: Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system. J Neurosci Res 36:681–693 1993

14.

Giulian DRobertson C: Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord. Ann Neurol 27:33421990Giulian D Robertson C: Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord. Ann Neurol 27:33–42 1990

15.

Holmin SSchalling MHöjeberg Bet al: Delayed cytokine expression in rat brain following experimental contusion. J Neurosurg 86:4935041997Holmin S Schalling M Höjeberg B et al: Delayed cytokine expression in rat brain following experimental contusion. J Neurosurg 86:493–504 1997

16.

Hopkins SJRothwell NJ: Cytokines and the nervous system I: expression and recognition. Trends Neurosci 18:83881995Hopkins SJ Rothwell NJ: Cytokines and the nervous system I: expression and recognition. Trends Neurosci 18:83–88 1995

17.

Hunt WEHess RM: Surgical risks as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 28:14201968Hunt WE Hess RM: Surgical risks as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 28:14–20 1968

18.

Jacobsson MOvergaard JMarcussen E: rCBF, AVDO2 and vasospasm in patients with subarachnoid hemorrhage: is vasospasm the actual cause of reduced cerebral uptake of oxygen? J Cereb Blood Flow Metab 7 (Suppl 1):S6601987 (Abstract)Jacobsson M Overgaard J Marcussen E: rCBF AVDO2 and vasospasm in patients with subarachnoid hemorrhage: is vasospasm the actual cause of reduced cerebral uptake of oxygen? J Cereb Blood Flow Metab 7 (Suppl 1):S660 1987 (Abstract)

19.

Jennett BTeasdale G: Management of Head Injuries. Philadelphia: FA Davis1981Jennett B Teasdale G: Management of Head Injuries. Philadelphia: FA Davis 1981

20.

Kassell NFHaley EC JrApperson-Hansen Cet al: Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg 84:2212281996Kassell NF Haley EC Jr Apperson-Hansen C et al: Randomized double-blind vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe Australia and New Zealand. J Neurosurg 84:221–228 1996

21.

Kim KSWass CACross ASet al: Modulation of blood-brain barrier permeability by tumor necrosis factor and antibody to tumor necrosis factor in the rat. Lymphokine Cytokine Res 11:2932981992Kim KS Wass CA Cross AS et al: Modulation of blood-brain barrier permeability by tumor necrosis factor and antibody to tumor necrosis factor in the rat. Lymphokine Cytokine Res 11:293–298 1992

22.

Lees GJ: The possible contribution of microglia and macrophages to delayed neuronal death after ischemia. J Neurol Sci 114:1191221993Lees GJ: The possible contribution of microglia and macrophages to delayed neuronal death after ischemia. J Neurol Sci 114:119–122 1993

23.

Liu TClark RKMcDonnell PCet al: Tumor necrosis factora expression in ischemic neurons. Stroke 25:148114881994Liu T Clark RK McDonnell PC et al: Tumor necrosis factora expression in ischemic neurons. Stroke 25:1481–1488 1994

24.

Liu TMcDonnell PCYoung PRet al: Interleukin-1β mRNA expression in ischemic rat cortex. Stroke 24:174617511993Liu T McDonnell PC Young PR et al: Interleukin-1β mRNA expression in ischemic rat cortex. Stroke 24:1746–1751 1993

25.

Maiuri FGallicchio BDonati Pet al: The blood leukocyte count and its prognostic significance in subarachnoid hemorrhage. J Neurosurg Sci 31:45481988Maiuri F Gallicchio B Donati P et al: The blood leukocyte count and its prognostic significance in subarachnoid hemorrhage. J Neurosurg Sci 31:45–48 1988

26.

Marzatico FGaetani PSilvani Vet al: Experimental isobaric subarachnoid hemorrhage: regional mitochondrial function during the acute and late phase. Surg Neurol 34:2943001990Marzatico F Gaetani P Silvani V et al: Experimental isobaric subarachnoid hemorrhage: regional mitochondrial function during the acute and late phase. Surg Neurol 34:294–300 1990

27.

Mathiesen TAndersson BLoftenius Aet al: Increased interleukin-6 levels in cerebrospinal fluid following subarachnoid hemorrhage. J Neurosurg 78:5625671993Mathiesen T Andersson B Loftenius A et al: Increased interleukin-6 levels in cerebrospinal fluid following subarachnoid hemorrhage. J Neurosurg 78:562–567 1993

28.

Mathiesen TFuchs DWachter Het al: Increased CSF neopterin levels in subarachnoid hemorrhage. J Neurosurg 73:69711990Mathiesen T Fuchs D Wachter H et al: Increased CSF neopterin levels in subarachnoid hemorrhage. J Neurosurg 73:69–71 1990

29.

Mathiesen TLefvert AK: Cerebrospinal fluid and blood lymphocyte subpopulations following subarachnoid haemorrhage. Br J Neurosurg 10:89921996Mathiesen T Lefvert AK: Cerebrospinal fluid and blood lymphocyte subpopulations following subarachnoid haemorrhage. Br J Neurosurg 10:89–92 1996

30.

Morimoto AWatanabe TSakata Yet al: Leukocytosis induced by microinjection of endogenous pyrogen or interleukin-1 into the preoptic and anterior hypothalamus. Brain Res 475:3453481988Morimoto A Watanabe T Sakata Y et al: Leukocytosis induced by microinjection of endogenous pyrogen or interleukin-1 into the preoptic and anterior hypothalamus. Brain Res 475:345–348 1988

31.

Neil-Dwyer GCruickshank J: The blood leucocyte count and its prognostic significance in subarachnoid haemorrhage. Brain 97:79861974Neil-Dwyer G Cruickshank J: The blood leucocyte count and its prognostic significance in subarachnoid haemorrhage. Brain 97:79–86 1974

32.

Pellettieri LNilsson BCarlsson CAet al: Serum immunocomplexes in patients with subarachnoid hemorrhage. Neurosurgery 19:7677711986Pellettieri L Nilsson B Carlsson CA et al: Serum immunocomplexes in patients with subarachnoid hemorrhage. Neurosurgery 19:767–771 1986

33.

Persson LHillered L: Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis. J Neurosurg 76:72801992Persson L Hillered L: Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis. J Neurosurg 76:72–80 1992

34.

Peterson JWKwun BDHackett JDet al: The role of inflammation in experimental cerebral vasospasm. J Neurosurg 72:7677741990Peterson JW Kwun BD Hackett JD et al: The role of inflammation in experimental cerebral vasospasm. J Neurosurg 72:767–774 1990

35.

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 71:7187261989Peterson JW Kwun BD Teramura A et al: Immunological reaction against the aging human subarachnoid erythrocyte. A model for the onset of cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg 71:718–726 1989

36.

Rothwell NJ: Functions and mechanisms of interleukin 1 in the brain. Trends Pharmacol Sci 12:4304361991Rothwell NJ: Functions and mechanisms of interleukin 1 in the brain. Trends Pharmacol Sci 12:430–436 1991

37.

Selmaj KWFarooq MNorton WTet al: Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. J Immunol 144:1291351990Selmaj KW Farooq M Norton WT et al: Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. J Immunol 144:129–135 1990

38.

Selmaj KWRaine CS: Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 23:3393461988Selmaj KW Raine CS: Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 23:339–346 1988

39.

Suzuki STakenaka KKassell NFet al: Hemoglobin augmentation of interleukin-1β—induced production of nitric oxide in smooth-muscle cells. J Neurosurg 81:8959011994Suzuki S Takenaka K Kassell NF et al: Hemoglobin augmentation of interleukin-1β—induced production of nitric oxide in smooth-muscle cells. J Neurosurg 81:895–901 1994

40.

Svendgaard NAArbab MADelgado TJet al: Effect of selective lesions of medullary cathecholamine nuclei on experimental cerebral vasospasm in the rat. J Cereb Blood Flow Metab 7:21281987Svendgaard NA Arbab MA Delgado TJ et al: Effect of selective lesions of medullary cathecholamine nuclei on experimental cerebral vasospasm in the rat. J Cereb Blood Flow Metab 7:21–28 1987

41.

Tchelingerian JLQuinonero JBooss Jet al: Localization of TNF-α and IL-1α immunoreactivities in striatal neurons after surgical injury to the hippocampus. Neuron 10:2132241993Tchelingerian JL Quinonero J Booss J et al: Localization of TNF-α and IL-1α immunoreactivities in striatal neurons after surgical injury to the hippocampus. Neuron 10:213–224 1993

42.

Waage AHalstensen AShalaby Pet al: Local production of tumor necrosis factor α, interleukin 1 and interleukin 6 in meningococcal meningitis. Relation to the inflammatory response. J Exp Med 170:185918671989Waage A Halstensen A Shalaby P et al: Local production of tumor necrosis factor α interleukin 1 and interleukin 6 in meningococcal meningitis. Relation to the inflammatory response. J Exp Med 170:1859–1867 1989

43.

Walton JN: Subarachnoid Hemorrhage. Edinburgh: ES Livingstone1956Walton JN: Subarachnoid Hemorrhage. Edinburgh: ES Livingstone 1956

44.

Weir BDisney LGrace Met al: Daily trends in white blood cell count and temperature after subarachnoidal hemorrhage from aneurysm. Neurosurgery 25:1611651989Weir B Disney L Grace M et al: Daily trends in white blood cell count and temperature after subarachnoidal hemorrhage from aneurysm. Neurosurgery 25:161–165 1989

45.

Weir BGrace MHansen Jet al: Time course of vasospasm in man. J Neurosurg 48:1731781978Weir B Grace M Hansen J et al: Time course of vasospasm in man. J Neurosurg 48:173–178 1978

46.

Wilkins RH: Cerebral vasospasm. Crit Rev Neurobiol 6:51771990Wilkins RH: Cerebral vasospasm. Crit Rev Neurobiol 6:51–77 1990

47.

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 33:2272361991Woodroofe MN Sarna GS Wadhwa M et 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 33:227–236 1991

48.

Yabuuchi KMinami MKatsumata Set al: An in situ hybridization study on interleukin-1 beta mRNA induced by transient forebrain ischemia in the rat brain. Mol Brain Res 26:1351421994Yabuuchi K Minami M Katsumata S et al: An in situ hybridization study on interleukin-1 beta mRNA induced by transient forebrain ischemia in the rat brain. Mol Brain Res 26:135–142 1994

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 7 7 4
Full Text Views 63 63 26
PDF Downloads 49 49 6
EPUB Downloads 0 0 0

PubMed

Google Scholar