(Stroke. 1995;26:676-681.)
© 1995 American Heart Association, Inc.
Articles |
Interleukin-1 as a Pathogenetic Mediator of Ischemic Brain Damage in Rats
From the Department of Neurology, Institute of Brain Disease, Tohoku University School of Medicine, Sendai, Miyagi (Y.Y., H.S., H.O., Y.I.); the Hanno Research Center, Taiho Pharmaceutical Co Ltd, Hanno, Saitama (N.M.); and the Institute of Neuropathology, Kumagaya, Saitama (K.K.), Japan.
Correspondence to Y. Yamasaki, Department of Neurology, Institute of Brain Disease, Tohoku University School of Medicine, Sendai, Miyagi 980, Japan.
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Abstract |
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Background and Purpose It has been suggested that interleukin-1 (IL-1) is a potent inflammatory mediator and that it is synthesized and secreted into the brain parenchyma. The aim of the present study is to evaluate the contribution of IL-1 to brain edema formation after focal brain ischemia.
Methods The brain water content was measured to evaluate postischemic brain injury in rats after 60 minutes of middle cerebral artery occlusion and reperfusion. The effects of exogenous application of recombinant human interleukin-1ß (rhIL-1ß), anti–interleukin-1ß neutralizing antibodies (anti–IL-1ß), and the IL-1 blocker zinc protoporphyrin (ZnPP) on brain water content were observed, and histological technique was used to measure the infarction size and number of inflammatory cells infiltrated into the brain.
Results Transient ischemia induced marked increase of brain water content, necrosis, and neutrophilic infiltration in the cortex perfused by the middle cerebral artery and the dorsal and ventral areas of the caudate putamen. Injection of rhIL-1ß into the left lateral ventricle immediately after reperfusion markedly enhanced ischemic brain edema formation in these three areas in a dose-dependent manner (88.4±0.7% and 86.6±0.4% in the dorsal and ventral parts of the caudate putamen, respectively, in rats treated with 10 ng rhIL-1ß; P<.01). rhIL-1ß also increased the size of the brain infarction, and it tended to increase the number of infiltrating neutrophils in ischemic areas and the number of neutrophils adherent to the endothelium. In contrast, administration of anti–IL-1ß and ZnPP into the left cerebral ventricle attenuated the postischemic increase of brain water content and decreased the size of brain infarction (83.5±2.0% and 79.9±2.0% in the dorsal and ventral parts of the caudate putamen, respectively, in rats treated with 10 µg anti–IL-1ß; P<.01). The number of neutrophils that infiltrated into ischemic areas also tended to decrease with anti–IL-1ß or ZnPP treatment.
Conclusions Application of rhIL-1ß augmented the increase of brain water content, and application of anti–IL-1ß depressed the increase of water content. These results tended to correlate with the neutrophilic infiltration into the parenchyma. It thus appears that IL-1ß may play an important role in ischemic brain damage after reperfusion.
Key Words: brain edema • cerebral ischemia, focal • interleukins • rats
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Introduction |
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Several lines of evidence have indicated that an inflammatory reaction is involved in ischemia-reperfusion injury and that chemical mediators released from leukocytes play an important role in this reaction.1 2 We previously reported that depletion of neutrophils markedly reduced the degree of ischemic brain damage.3 Interleukin 1 (IL-1) is a potent inflammatory mediator that is also known to be a cofactor in inflammatory reaction. Since IL-1ß is detected in the traumatized mammalian brain and is a potent astroglial growth factor, IL-1ß may regulate astroglial proliferation at the site of central nervous system injury.4 5 Moreover, IL-1ß injected into the brain has various biological effects, such as fever, slow-wave sleep, and suppression of food intake.6 7 Furthermore, McClain et al8 reported that IL-1 was present in the ventricular fluid of patients with traumatic brain injury. Although the cellular sources of brain IL-1ß remain uncertain, amoeboid microglia and/or astroglia have been suggested to be the main sources of IL-1ß in the central nervous system.9 Blood monocytes that enter the brain after brain injury might also be a source of IL-1ß in the brain.10 These reports clearly indicate that IL-1ß at least in part contributes to brain damage after trauma and ischemia. Recently, IL-1ß mRNA was detected in ischemic brains in a four-vessel occlusion model and in a focal permanent ischemic model in rats.11 12 These reports lend additional credence to the idea that IL-1ß production is involved in ischemic brain damage. However, few studies have focused on the role of IL-1ß in postischemic brain damage or on the issue of whether IL-1ß inhibitors can ameliorate ischemic brain damage. In the present study, we assessed the contribution of IL-1ß to ischemic brain edema formation in rats by application of recombinant IL-1ß, selective IL-1 blocker, and anti–IL-1ß neutralizing antibodies.
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Materials and Methods |
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One hundred twenty adult male Wistar rats, weighing 270 to 320 g, were purchased from Japan SLC, Inc, and allowed free access to food and water. Transient focal cerebral ischemia was induced using a slightly modified version of the method of Zea Longa et al,13 as has been described previously. Briefly, each rat was anesthetized with a gas mixture of N2O/O2 (70:30) containing 2% halothane. After a median incision of the neck skin, the right external carotid artery was carefully dissected; an 18-mm-long 4-0 nylon thread precoated with silicon was inserted from the external carotid artery lumen to the right internal carotid artery lumen to occlude the origin of the right middle cerebral artery (MCA). The body temperature was measured with a rectal thermometer and was kept at 37±1°C using a heating pad with a thermostat during the operation and until reappearance of righting reflex to minimize the effect of body temperature on ischemic brain damage. After 60 minutes of MCA occlusion, the thread was then removed to allow complete reperfusion of the ischemic area through the right common carotid artery. Neurological deficits characterized by severe left-sided hemiparesis and right-sided Horner's syndrome were used as the criteria for evaluating the ischemic insult. One day after reperfusion, the rats were decapitated; the brain samples were dissected into the cerebral cortex perfused by the MCA (MCA area) and the dorsal and ventral areas of the caudate putamen (DCP and VCP, respectively) in a humidified glove box. To assess the brain water content, brain samples were dried in an oven at 110°C for 24 hours, and water content of these samples was then measured by the dry-weight method.14
To evaluate the contribution of IL-1ß to the brain edema formation, 2 µL of each of the agents listed below was topically applied to the right cerebral ventricle immediately after reperfusion over a period of 4 minutes, with the needle left in place for 2 minutes thereafter. The agents were (1) recombinant human IL-1ß (rhIL-1ß; kindly donated by Otsuka Pharmaceutical Co, Ltd) diluted with phosphate-buffered saline (PBS); (2) polyclonal anti-mouse IL-1ß neutralizing antibodies (immunoglobulin G [IgG] fraction, anti–IL-1, R & D Systems Inc) that were produced in goats immunized with IL-1ß, diluted with PBS; or (3) the disodium salt of zinc protoporphyrin, an IL-1 blocker (ZnPP; Aldrich; converted to a disodium salt by standard methods), dissolved in saline. PBS or saline was injected into the cerebral ventricle in the vehicle group. The coordinates of the injection site were as follows: 0.8 mm posterior to the bregma, 1.5 mm lateral to the midline, and 4.5 mm depth from the dural surface, according to the atlas.15 To deplete peripheral blood leukocytes, x-ray irradiation treatment (11 Gy; MBR-1505R, Hitachi) was applied 4 days before the induction of ischemia; peripheral leukocyte count was decreased from 7x105/dL to 9x104/dL.
For statistical analysis, Dunnett's multiple test was used for comparison of the results in each group.
For the histological analysis, the rats were anesthetized with sodium pentobarbital and then perfused transcardially with PBS followed by 4% buffered paraformaldehyde 24 hours after recirculation. The brain of each rat was then removed, postfixed, and embedded in paraffin. For evaluation of the size of infarction areas and the neutrophilic infiltration status, brain sections (5 µm thick) were stained with hematoxylin and eosin. The size of the infarction areas in the ischemic hemisphere was measured using a color image analyzer (Olympus SP500).
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Results |
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Effect of Recombinant Human IL-1ß in Normal and Ischemic Brain Damage
Ischemia for 60 minutes followed by 24-hour reperfusion resulted in reproducible infarction and severe neuronal damage to the DCP and MCA and moderate damage to the VCP.
In normal rats, the brain water content of the MCA, DCP, and VCP was
79.0±0.1%, 76.6±0.3%, and 76.6±0.2%, respectively (n=7,
mean±SEM). Twenty-four hours after reperfusion, the water content was
85.5±0.3%, 86.0±0.3%, and 83.9±0.4%, respectively (n=6).
Injection of rhIL-1ß immediately after reperfusion resulted in a
dose-dependent increase of the water content of the DCP and VCP 24
hours after reperfusion. As shown in Fig 1
, rhIL-1ß at
a dose of 10 ng significantly increased the water content of the DCP
and VCP to 88.4±0.7% and 86.6±0.4%, respectively (n=5), but did not
significantly alter the water content of the MCA area. In contrast,
application of rhIL-1ß (10 or 100 ng, n=5) did not increase the water
content in normal rats (Fig 2).
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In the histological evaluation, the size of the infarction area
measured on coronal sections 1.7 mm, 0.7 mm, and -0.3 mm from the
bregma was 43.8±1.5%, 54.3±1.5%, and 59.9±2.0%, respectively
(n=5), in vehicle (PBS)-treated rats. Injection of rhIL-1ß at a dose
of 10 ng significantly increased the sizes of infarction areas measured
on all sections examined (Fig 3).
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Although neutrophils were not observed in the MCAs, DCPs, or VCPs of
the normal rats, several areas of neutrophil accumulation were observed
in the perivascular spaces in the DCP and MCA on the occluded side 24
hours after ischemia. In the rhIL-1ß–treated rats, the number of
neutrophils infiltrated into the brain parenchyma and the number of
neutrophils attached to the endothelium was, for both counts, 95±17
cells per section (mean±SEM, n=5) in the section at -0.3 mm from the
bregma and tended to increase in comparison with vehicle-treated rats
(76±12 cells per section, mean±SEM, n=5; Fig 4).
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Effects of IL-1ß Inhibitor and Anti–IL-1ß Antibodies on
Ischemic Brain Damage
Injection of anti-mouse IL-1ß neutralizing polyclonal antibodies
(goat IgG fraction, anti–IL-1ß) reduced the brain water content in
the DCP, VCP, and MCA 24 hours after reperfusion in a dose-dependent
manner. Anti–IL-1ß antibodies at a dose of 10 µg, which is
sufficient to neutralize IL-1 with more than 5 U/mL activity in vitro,
significantly reduced edema formation. The water content of the MCA,
DCP, and VCP in the group treated with anti–IL-1ß was 82.0±2.0%,
83.5±2.0%, and 79.9±2.0%, respectively (n=5, Fig 5).
Injection of preimmune goat IgG (10 µg) failed to reduce the water
content (n=5). Thus, an ameliorating effect of anti–IL-1ß antibodies
could be induced by specific blocking of IL-1ß activity. Furthermore,
ZnPP at doses of 1 and 10 µg significantly suppressed brain edema
formation in the DCP and the VCP in a dose-dependent manner (n=5, Fig 6). However, brain edema in the MCA area was not
significantly reduced with ZnPP treatment (10 µg). The water content
in the DCP, VCP, and MCA was 84.5±0.4%, 83.6±0.3%, and 79.9±2.0%,
respectively, in the group treated with ZnPP (10 µg).
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In the histological evaluation, application of anti–IL-1ß (10 µg)
significantly reduced the size of infarction areas. Furthermore, the
number of infiltrating neutrophils in the brain was 56±14 cells per
section (mean±SEM, n=5) in the section at -0.3 mm from the bregma in
the rats treated with IL-1ß antibodies and tended to decrease in
comparison to the number in vehicle-treated rats (Figs 3
and 4).
Effect of Recombinant Human IL-1ß and Anti–IL-1ß Antibodies on
Ischemic Brain Damage After Irradiation Treatment
In irradiated rats, on the day of ischemia, the peripheral
leukocyte count was decreased to 9x104/dL. All
numbers of constituent cells, neutrophils, lymphocytes, and monocytes
were decreased, and percentages of leukocytes remained unchanged in
comparison to those in nontreated rats. No detectable physiological
abnormalities were observed in irradiated rats. Ischemic brain edema
formation was significantly decreased; the brain water content in the
MCA, DCP, and VCP was 81.7±1.8%, 83.7±1.2%, and 80.8±1.3%,
respectively (n=5, Fig 7). Injection of rhIL-1ß at a
concentration of 10 ng in irradiated rats significantly increased brain
water content compared with that of the vehicle-treated irradiated rats
(n=5). Brain water content in the irradiated rats was almost the same
as that in the nontreated rats. In irradiated rats treated with
anti–IL-1ß antibodies (10 µg), brain water content in each area
was decreased compared with that in irradiated rats treated with
vehicle (n=5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We observed in the present study that IL-1ß mediates inflammatory responses after ischemic brain injury. High concentration of rhIL-1ß has been reported to induce brain edema and astrogliosis even in normal rats.4 16 In addition, IL-1 has been detected in the rat brain 1 to 4 days after traumatic damage and in the cerebroventricular fluid of patients suffering from traumatic brain injury.10 Taken together, these results suggest that IL-1 is an important factor in postischemic brain damage. To ascertain the possible contribution of IL-1 to ischemic brain edema, we studied the effect of IL-1ß on brain edema formation by applying rhIL-1ß, anti–IL-1ß antibodies, and IL-1 blocker. IL-1 has two structurally distinct forms,
and ß, both of which recognize the same receptor.
Autoradiographic and immunohistochemical analytic results for IL-1
binding sites in the brain indicate that in rats IL-1ß binding
apparently predominates. The present results revealed that rhIL-1ß augmented the increase in brain water content after ischemia, especially in the caudate putamen. The augmentation of brain water content was well correlated with that of the sizes of infarction in the ischemic hemisphere. Furthermore, treatment with rhIL-1ß tended to increase the infiltration and adhesion of neutrophils in ischemic areas. On the other hand, anti–IL-1ß reduced the ischemic brain water content and the size of infarction in the ischemic hemisphere. The reduction of infarct size was accompanied by a decrement in the number of infiltrated neutrophils in ischemic areas. Iannotti12 has reported that IL-1ß increased from 63 to 195 µg/mg protein after incomplete continuous ischemia and that this increase took place even in 30 minutes of ischemia; Giulian et al10 reported that fluid-percussion injury also induced IL-1 production to a concentration of over 10 U/mg 3 to 18 hours after injury. Since the anti–IL-1ß antibodies used in the present study neutralize IL-1 with more than 5 U/mL activity, we consider the dose of anti–IL-1ß antibodies used to be a reasonable dose for blocking IL-1ß activity. ZnPP, an IL-1 blocker, reduced the ischemic brain edema formation in a dose-dependent manner. We previously observed that ZnPP blocked IL-1 activity using an in vitro thymocyte proliferation system at low concentration.18 Although fever has been ascribed to the action of prostaglandins or IL-1ß in the hypothalamus,19 the treatment with anti–IL-1ß antibodies or ZnPP did not affect the body temperature.
IL-1 is an acknowledged direct and indirect chemoattractant to polymorphonuclear cells and plays an important role in induction of adhesion molecules.20 21 The transient nature of polymorphonuclear cells at sites of inflammation might indicate their rapid response to activation signals associated with prompt elevation and decline in cytokine production. Hence, invading neutrophils, probably activated at the site of brain injury, may make a major contribution to the production of these immune mediators. Hallenbeck et al20 indicated that the local leukocyte accumulation and coagulation were correlated with the local synthesis of IL-1 in brain damage after stroke. We also have reported that depletion of circulating neutrophils by injection of anti–neutrophil antibody reduced ischemic brain edema in a rat model, and we concluded that infiltrating neutrophils play a critical role in the formation of brain edema in reperfusion injury.3 A tendency for reduction of neutrophil infiltration by the inhibition of IL-1ß activity was shown in the present study. Furthermore, injection of rhIL-1ß at higher doses could not induce brain edema formation. This might indicate that IL-1 may synergistically act with other proinflammatory mediators, such as leukotriene or platelet-activating factor in the formation of edema.
Another unresolved issue is the source of IL-1 in the ischemic brain. Endogenous brain cells, activated by this injury, may release several kinds of cytokines. This possibility is supported by studies demonstrating that activation of microglial cells can be observed after traumatic brain lesions. The astrocytic responses after injury are observed much later than the peak level of IL-1 production.22 Therefore, IL-1 may be produced by microglia at the site of brain injury and may also propagate astrocytic reactions. Furthermore, immunohistochemical analysis has revealed that neuronal elements have the capacity to synthesize and probably secrete IL-1. The present data in rats with irradiation-induced leukopenia also indicate that anti–IL-1ß antibodies suppress elevation of brain water content. We cannot rule out the possibility that the increase in IL-1 observed after ischemia is due to production by microglia, astroglia, neurons, or endothelial cells. Further investigations are needed to determine the intracerebral source or sources of IL-1 and the sites of IL-1 receptors.
In conclusion, IL-1 plays a crucial role in the development of ischemic brain injury. It is important to develop peripherally administered agents that selectively suppress the IL-1 activity in the areas with ischemic damage.
Received June 21, 1994; revision received December 1, 1994; accepted December 29, 1994.
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 M. Monroy, J. W. Kuluz, D. He, W. D. Dietrich, and C. L. Schleien Role of nitric oxide in the cerebrovascular and thermoregulatory response to interleukin-1{beta} Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1448 - H1453. [Abstract] [Full Text] [PDF]
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N. Vila, J. Castillo, A. Davalos, and A. Chamorro Proinflammatory Cytokines and Early Neurological Worsening in Ischemic Stroke Stroke, October 1, 2000; 31(10): 2325 - 2329. [Abstract] [Full Text] [PDF]
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W. M. Clark, L. G. Rinker, N. S. Lessov, K. Hazel, J. K. Hill, M. Stenzel-Poore, F. Eckenstein, and E. C. Haley Jr Lack of Interleukin-6 Expression Is Not Protective Against Focal Central Nervous System Ischemia Editorial Comment Stroke, July 1, 2000; 31(7): 1715 - 1720. [Abstract] [Full Text] [PDF]
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 A Leskovar, L. Moriarty, J. Turek, I. Schoenlein, and R. Borgens The macrophage in acute neural injury: changes in cell numbers over time and levels of cytokine production in mammalian central and peripheral nervous systems J. Exp. Biol., January 6, 2000; 203(12): 1783 - 1795. [Abstract] [PDF]
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A. Vezzani, M. Conti, A. De Luigi, T. Ravizza, D. Moneta, F. Marchesi, and M. G. De Simoni Interleukin-1beta Immunoreactivity and Microglia Are Enhanced in the Rat Hippocampus by Focal Kainate Application: Functional Evidence for Enhancement of Electrographic Seizures J. Neurosci., June 15, 1999; 19(12): 5054 - 5065. [Abstract] [Full Text] [PDF]
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 N. J Rothwell Cytokines - killers in the brain? J. Physiol., January 1, 1999; 514(1): 3 - 17. [Abstract] [Full Text] [PDF]
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F. C. Barone, R. F. White, P. A. Spera, J. Ellison, R. W. Currie, X. Wang, G. Z. Feuerstein, and N. J. Rothwell Ischemic Preconditioning and Brain Tolerance: Temporal Histological and Functional Outcomes, Protein Synthesis Requirement, and Interleukin-1 Receptor Antagonist and Early Gene Expression • Editorial Comment Stroke, September 1, 1998; 29(9): 1937 - 1951. [Abstract] [Full Text] [PDF]
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 N. J. Rothwell REVIEW {blacksquare} : Interleukin-1 and Neurodegeneration Neuroscientist, May 1, 1998; 4(3): 195 - 201. [Abstract] [PDF]
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 L. Pantoni, C. Sarti, and D. Inzitari Cytokines and Cell Adhesion Molecules in Cerebral Ischemia : Experimental Bases and Therapeutic Perspectives Arterioscler Thromb Vasc Biol, April 1, 1998; 18(4): 503 - 513. [Abstract] [Full Text] [PDF]
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J. A. Clemens, D. T. Stephenson, T. Yin, E. B. Smalstig, J. A. Panetta, S. P. Little, W. D. Dietrich, and J. Bethea Drug-Induced Neuroprotection From Global Ischemia Is Associated With Prevention of Persistent but Not Transient Activation of Nuclear Factor-{kappa}B in Rats • Editorial Comment Stroke, March 1, 1998; 29(3): 677 - 682. [Abstract] [Full Text] [PDF]
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L. Wang, N. D. Tran, M. Kittaka, M. J. Fisher, S. S. Schreiber, and B. V. Zlokovic Thrombomodulin Expression in Bovine Brain Capillaries : Anticoagulant Function of the Blood-Brain Barrier, Regional Differences, and Regulatory Mechanisms Arterioscler Thromb Vasc Biol, November 1, 1997; 17(11): 3139 - 3146. [Abstract] [Full Text]
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 A. Martin-Ancel, A. Garcia-Alix, D. Pascual-Salcedo, F. Cabanas, M. Valcarce, and J. Quero Interleukin-6 in the Cerebrospinal Fluid After Perinatal Asphyxia Is Related to Early and Late Neurological Manifestations Pediatrics, November 1, 1997; 100(5): 789 - 794. [Abstract] [Full Text] [PDF]
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J. A. Clemens, D. T. Stephenson, E. B. Smalstig, E. P. Dixon, and S. P. Little Global Ischemia Activates Nuclear Factor-{kappa}B in Forebrain Neurons of Rats Stroke, May 1, 1997; 28(5): 1073 - 1081. [Abstract] [Full Text]
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 H. Hara, R. M. Friedlander, V. Gagliardini, C. Ayata, K. Fink, Z. Huang, M. Shimizu-Sasamata, J. Yuan, and M. A. Moskowitz Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage PNAS, March 4, 1997; 94(5): 2007 - 2012. [Abstract] [Full Text] [PDF]
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J. D. Lutton, N. G. Abraham, G. S. Drummond, R. D. Levere, and A. Kappas Zinc porphyrins: Potent inhibitors of hematopoieses in animal and human bone marrow PNAS, February 18, 1997; 94(4): 1432 - 1436. [Abstract] [Full Text] [PDF]
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X. Wang, F. C. Barone, N. V. Aiyar, G. Z. Feuerstein, and G. J. del Zoppo Interleukin-1 Receptor and Receptor Antagonist Gene Expression After Focal Stroke in Rats Stroke, January 1, 1997; 28(1): 155 - 162. [Abstract] [Full Text]
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S. M. Allan, L. C. Parker, B. Collins, R. Davies, G. N. Luheshi, and N. J. Rothwell Cortical cell death induced by IL-1 is mediated via actions in the hypothalamus of the rat PNAS, May 9, 2000; 97(10): 5580 - 5585. [Abstract] [Full Text] [PDF]
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