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(Stroke. 1996;27:1553-1557.)
© 1996 American Heart Association, Inc.

Articles

Serial Measurement of Interleukin-6, Transforming Growth Factor-ß, and S-100 Protein in Patients With Acute Stroke

Jong S. Kim, MD; Sung S. Yoon, RN; Yang H. Kim, MS Jin S. Ryu, MD

the Departments of Neurology (J.S.K., S.S.Y.) and Nuclear Medicine (J.S.R.), University of Ulsan, Asan Medical Center; and the Asan Life Science Institute (J.S.K., Y.H.K), Seoul, South Korea.

Correspondence to Jong S. Kim, MD, Department of Neurology, Asan Medical Center, Song-Pa PO Box 145, Seoul 138-600, South Korea.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Cytokine changes in patients with acute stroke have been insufficiently studied. The purpose of this study was to delineate the characteristics of serial changes of serum interleukin-6 (IL-6) and transforming growth factor-ß (TGF-ß) in patients with cerebral infarction and intracerebral hemorrhage.

Methods We serially (within 24 hours, at day 3, and at day 7) measured the serum levels of IL-6 and TGF-ß in 29 patients with acute stroke (10 with large cortical cerebral infarction, 9 with subcortical small infarction, and 10 with intracerebral hemorrhage). As an index of brain damage, S-100 protein was also measured. Twelve age-matched healthy subjects were tested as a control.

Results S-100 protein was detected in only 11 patients with large infarction or intracerebral hemorrhage. Its level peaked at day 3 in patients with infarction, whereas it peaked within 24 hours in those with intracerebral hemorrhage. The level of IL-6 was most markedly elevated at day 1, which tended to decrease thereafter. However, its level remained significantly elevated compared with that of the control group even at day 7. The level of TGF-ß was significantly decreased at day 1 and day 3 and tended to return toward the control value thereafter. The levels of both cytokines were not significantly different among the three different stroke subtypes and were not correlated with the number of blood leukocytes and platelets.

Conclusions The alteration of IL-6 and TGF-ß levels, which occurs rapidly after acute stroke regardless of the subtype, may reflect the changing immunological-inflammatory status of these patients and does not appear to reflect merely the consequence of the brain damage.

Key Words: cytokines • interleukins • stroke • transforming growth factors

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Recently, various cytokines,^{1 2 3 4 5} chemokines,^{6 7 8} and adhesion molecules^{9 10 11} have been shown to be expressed in the ischemic brain of experimental animals. A few studies also have revealed increased levels of certain cytokines^{12 13 14} and adhesion molecules^{15 16} in the body fluids of patients with ischemic stroke. These experimental and human data suggest that cytokines and adhesion molecules are involved in the pathogenesis of stroke and related diseases.¹⁷

However, the data on humans obtained thus far are still insufficient, and serial and concomitant measurements reflecting proinflammatory and anti-inflammatory cytokines have not been carried out. Furthermore, previous reports emphasize only the patients with cerebral infarction, and those patients with ICH are largely neglected. The purpose of this study was to investigate the changes of proinflammatory and immunomodulatory cytokines in various subtypes of stroke.

IL-6, one of the few cytokines measurable in human serum, is stimulated by proinflammatory cytokines TNF- and IL-1, and it appears to reflect the proinflammatory status of patients with acute stroke.¹³ On the other hand, TGF-ß is a well-known immunomodulatory cytokine. Therefore, in the present study, we simultaneously and serially measured serum levels of IL-6 and TGF-ß in patients with acute stroke including cerebral infarction and ICH. Furthermore, we also wished to elucidate whether the changes of these cytokines reflect merely a consequence of brain damage or represent an actively occurring phenomenon. To resolve this issue, we concomitantly measured the serum level of S-100 protein and compared the changing pattern of this protein with that of cytokines. Although still in the experimental stage, S-100 protein has been shown to reflect best, among other brain-specific proteins, the degree of cerebral injury.^{18 19 20 21 22}

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We studied 36 patients with acute stroke (within 24 hours after onset) who were admitted at Asan Medical Center between September 1994 and July 1995. Excluded were patients with (1) history of recent (within 2 weeks before admission) infection; (2) concurrent major cardiac, renal, hepatic, and cancerous diseases; (3) stroke due to aneurysmal rupture, arteriovenous malformations, moyamoya disease, and other vascular malformations; (4) recent (within 1 month) history of head trauma; (5) transient ischemic attack; (6) CT and/or MRI results that were inconclusive for the lesion location; and (7) obvious signs of acquired infection after admission.

All patients were evaluated with CT and/or MRI. According to the clinical history and imaging results, the patients were classified as having LI (largest diameter of infarct >4 cm), SI (largest diameter of infarct <1.5 cm), and ICH. The 7 patients with infarct sizes slightly greater than 1.5 cm were not tested because their vascular pathogenesis was unclear.

Patients' blood was serially drawn through the antecubital vein at three times: within 24 hours (as soon as the patients were examined), at day 3, and at day 7. Samples were immediately centrifuged (1500g, 10 minutes), and the sera were stored at -60°C until used. At the time of first sampling, peripheral leukocytes and platelets were simultaneously counted. Serum levels of IL-6 and TGF-ß were measured with commercially available quantitative "sandwich" enzyme-linked immunosorbent assay (Quantikine) kits obtained from R&D System for IL-6 and from Genzyme for TGF-ß with the use of antibodies specific for these cytokines. The lower limits of detection were 3.13 pg/mL for IL-6 and 0.1 ng/mL for TGF-ß.

Serum S-100 protein was measured with a two-site immunoradiometric assay kit (Sangtec S-100, IRMA, Sangtec Medical). Each patient's sample (100 µL) and diluent (100 µL; phosphate buffer with bovine serum albumin) were incubated with a plastic bead coated with monoclonal antibody to S-100 for 1 hour at room temperature on a shaker. The bead was then washed to remove unbound material and incubated with 200 µL of tracer (¹²⁵I-labeled monoclonal antibody to S-100) for 2 hours. After unreacted radioactive antibody was washed off the bead, the radioactivity bound to the bead was measured with a gamma counter. The minimum measurable S-100 value was 0.3 µg/L.

Twelve age-matched healthy control subjects were recruited from those who visited Asan Medical Center for routine health check-ups. For statistical analysis, we used Student's t test, ANOVA, and Pearson correlation coefficients, with the use of an SAS software package. All data were expressed as mean±SEM.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients
Twenty-nine patients (16 men and 13 women, aged 46 to 86 [mean, 63] years) and 12 control subjects were studied. Ten patients had LI, of whom 1 with atrial fibrillation was considered to have a stroke due to cardiac embolism. Nine patients had SI, and 10 had ICH. The demographic characteristics, risk factors, and the leukocyte and platelet counts at the time of first sampling are summarized in the Table. The number of initial blood leukocytes was higher in patients with LI and SI compared with the control subjects (P<.05). The platelet count of the patients was not different from that of control subjects. However, the number of platelets in the patients with LI was significantly lower than that of the patients with SI (P<.05). Three patients with LI underwent angiography; one was treated with intra-arterial urokinase. Other patients with cerebral infarction were generally treated with anticoagulation. Five patients with LI died during hospitalization.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Patient Subgroups

Serum Level of IL-6
Generally, the level of IL-6 in patients with stroke was significantly higher than that of the control group at all time points (Fig 1); the average levels of IL-6 were 49±16 pg/mL at day 1, 14±3 pg/mL at day 3, and 14±4 pg/mL at day 7, all of which were significantly elevated (in all, P<.05) compared with the control value (1.3±0.3 pg/mL). The serum IL-6 level obtained at day 1 was significantly higher than those measured at day 3 and day 7 (P<.05).

View larger version (24K): [in this window] [in a new window]   Figure 1. Serum level of IL-6 in patients with stroke. Data are expressed as mean±SEM. *P<.05 versus control; +P<.05 versus value at day 1.

Among different stroke subgroups, the average values obtained at day 1, day 3, and day 7, respectively, were 90±39, 9±3, and 10±3 pg/mL for the patients with LI; 28±16, 12±7, and 10±3 pg/mL for those with SI; and 27±16, 19±6, and 21±11 pg/mL for those with ICH. Although the serum IL-6 level at day 1 was the highest in patients with LI, the difference in value among stroke subtypes was not statistically significant at any time point (Fig 2). The level of IL-6 at day 1 was not correlated with the number of peripheral leukocytes (r=.62) and platelets (r=.58).

View larger version (20K): [in this window] [in a new window]   Figure 2. Serum level of IL-6 in patients with stroke of different subtypes. Data are expressed as mean±SEM.

Serum Level of TGF-ß
The average levels of TGF-ß in patients with stroke were 79±9 ng/mL at day 1, 72±8 ng/mL at day 3, and 96±15 ng/mL at day 7. The values at day 1 and day 3 were significantly lower (P<.05) than the control value (117±15 ng/mL) (Fig 3).

View larger version (42K): [in this window] [in a new window]   Figure 3. Serum level of TGF-ß in patients with stroke. Data are expressed as mean±SEM. *P<.05 versus control.

Among stroke subgroups, the average values at day 1, day 3, and day 7, respectively, were 84±12, 79±13, and 106±32 ng/mL for the patients with LI; 78±17, 92±10, and 89±21 ng/mL for those with SI; and 75±18, 48±16, and 94±28 ng/mL for those with ICH. The values among different stroke subtypes were not significantly different at any time point, although the value at day 3 from patients with ICH was the lowest (Fig 4). The level of TGF-ß at day 1 was not correlated with the number of leukocytes (r=.67), number of platelets (r=.72), or IL-6 level (r=.82).

View larger version (32K): [in this window] [in a new window]   Figure 4. Serum level of TGF-ß in patients with stroke of different subtypes. Data are expressed as mean±SEM.

Serum Level of S-100 Protein
The S-100 protein level was measurable (>0.3 µg/L) in only 11 patients: 7 patients with LI (including all 5 who died during hospitalization) and 4 patients with ICH. It was measurable in none of the patients with SI. The level peaked at day 3 in 6 patients with LI and within 24 hours in all patients with ICH (Fig 5).

View larger version (26K): [in this window] [in a new window]   Figure 5. Serum level of S-100 in patients with large infarction (top) and ICH (bottom). Each curve represents an individual patient.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We found that the serum level of IL-6 was elevated in the patients with acute stroke that peaked within 24 hours. At day 7, it still remained significantly elevated. Although other workers have reported similar results,^{12 13 14} our study is the first showing that patients with primary ICH also had a similar pattern of elevated serum IL-6. In accordance with previous reports, its level was highest in patients with LI, but the difference among stroke subgroups was not statistically significant.

To the best of our knowledge, ours is the first attempt that measured the serum level of TGF-ß in patients with acute stroke. TGF-ß mRNA and proteins have been shown to be expressed in the damaged brain.²³ We found unexpectedly that the level of this cytokine was decreased in an acute stage of stroke compared with that in the control subjects. The degree of the decrement and the temporal pattern of the cytokine changes were similar among different subtypes of stroke, although patients with ICH showed a nonsignificant trend to have a lower level of TGF-ß at day 3.

The cellular sources of the serum IL-6 and TGF-ß remain unknown. Peripheral leukocytes that increased in number after acute stroke^{24 25 26 27 28} could be the source of these cytokines.^{29 30 31} In our study, however, the number of leukocytes was not correlated with the levels of these cytokines. Recently, Beamer et al¹³ reported that serum IL-6 levels in patients with acute ischemic stroke correlated with the number of peripheral monocytes, which unfortunately we did not measure. Platelets are a significant source of circulating TGF-ß^{30 31} and were shown to be reduced in number in patients with acute stroke in a previous study.²⁷ In our study, however, the platelet count of the patients did not differ from that of control subjects, and it was not correlated with the serum level of TGF-ß. Recent demonstrations of a much higher level of IL-6 in the cerebrospinal fluid than in the serum of patients with stroke¹⁴ or head injury³² suggested that the cellular origin of serum cytokines in these patients may be the central nervous system. Brain cells, including the astrocytes, microglia, and neurons, were shown to produce IL-6^{33 34 35} and TGF-ß^{36 37 38} under certain pathological conditions.

IL-6 has both proinflammatory and immunomodulatory actions.^{39 40 41} The mRNA of this cytokine is expressed in a manner very similar to that of proinflammatory cytokines TNF- and IL-1 in rats subjected to middle cerebral artery occlusion.⁵ IL-6 is an important regulator of acute-phase reactants,^{39 40} and the serum level of this cytokine was found to be correlated with the level of C-reactive protein in patients with acute ischemic stroke,¹³ suggesting that serum IL-6 may reflect proinflammatory status after acute stroke. The fact that only IL-6 but not TNF- or IL-1 was measurable in the human serum^{12 14} may be consistent with the previous observation that IL-6 was more abundantly produced from the brain cells after certain stimulation compared with other cytokines.⁴²

Although TGF-ß was also shown to play a proinflammatory role by attracting inflammatory cells or upregulating certain integrins,²⁸ this cytokine has been considered to exert mainly an immunomodulatory role in pathological conditions.^{29 43} TGF-ß has a significant antagonistic effect against proinflammatory cytokine TNF-^{44 45} and also decreases the adherence of neutrophils to endothelial cells by reducing the expression of adhesion receptors.^{46 47}

Although the mechanism for the reduction of serum TGF-ß level in patients with acute stroke remains obscure, our data are consistent with a previous report that showed decreased levels of serum TGF-ß in patients with Plasmodium falciparum malaria infection.⁴⁸ A decreased level of immunomodulatory cytokine TGF-ß may reflect the proinflammatory status of the cytokine network after acute stroke. It could also be speculated that this cytokine was excessively utilized or accumulated in the tissue in the highly proinflammatory environment. Alternatively, since TGF-ß and IL-6 work synergistically in reducing recruitment of leukocytes due to endotoxin,⁴³ decreased TGF-ß might be a reciprocal depression in response to elevated IL-6. This, however, is unlikely because the IL-6 and TGF-ß levels were not correlated with each other.

In this study, we concomitantly measured the serum S-100, an acidic protein that was shown to be elevated in cerebrospinal fluid^{20 22} and, less markedly, in the serum of patients with various cerebral injuries.^{18 19 23} We found that the level peaked at day 3 in patients with LI, whereas it peaked within 24 hours in patients with ICH. Our results are consistent with a previous experimental study⁴⁹ reporting that the peak level of this protein was detected 2 to 4 days after middle cerebral artery occlusion, whereas the protein level peaked at about 7.5 hours in animals subjected to brain contusion. The delayed peak of S-100 in patients with LI appears to agree with the time course of vasogenic edema in patients with cerebral infarction. This observation, along with the fact that serum S-100 was detected only in patients with severe stroke, further supports the previous notion that the S-100 level reflects the actual brain damage.^{22 23} In our results, neither the peak of IL-6 nor the nadir of TGF-ß corresponds to the peak of S-100 in the patient with LI, and patients with SI showed a similar degree of serum cytokine changes as those with large stroke. Therefore, the alteration of the cytokines does not simply reflect (although it is influenced by¹³ ) the consequence of brain damage, but rather it represents an early actively occurring phenomenon that follows acute stroke.

Admittedly, the present study has several limitations. First, the patients with each subtype of stroke and the control subjects were not homogeneous in their gender and risk factors, and the baseline cytokine level of each group could therefore be different. Second, although we excluded patients who acquired obvious infection after hospitalization, factors such as transient urinary catheter insertion, tracheostomy, intravenous line, angiographic procedures, mental stress from the hospital admission, and various therapeutic modalities might have altered somewhat the cytokine levels in patient subgroups. Finally, the cytokines measured in human serum should reflect only a small portion of the proteins from yet unknown large sources of cytokines and thus require cautious interpretation. Nevertheless, the dynamically changing levels of serum cytokines as shown in this study, as well as previous ones,^{12 13 14 15 16} strongly suggest that cytokine/chemokine/adhesion molecule cascades do occur in patients with acute stroke.¹⁷ Further studies with larger numbers of patients are warranted.

	Selected Abbreviations and Acronyms

 

ICH = intracerebral hemorrhage IL = interleukin LI = large cortical infarct SI = small subcortical infarct TGF = transforming growth factor TNF = tumor necrosis factor

	Acknowledgments

 
This study was supported by grants from the Korean Science and Engineering Foundation and the Korean Institute of Science and Technology G7 Project for Technology Development.

Received December 13, 1995; revision received May 6, 1996; accepted May 6, 1996.

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