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Aging and disease    2016, Vol. 7 Issue (5) : 614-622     DOI: 10.14336/AD.2016.0207
Original Article |
Serum IL-33 Is a Novel Diagnostic and Prognostic Biomarker in Acute Ischemic Stroke
Qian Li1, Yuanshao Lin1, Wensi Huang1, Yulei Zhou1, Xiaoli Chen1, Brian Wang3, Wanli Zhang1, Zhengyi Cai1, Jie Xue1, Wenhui Zhang2, Tieer Yu1, Hong Wang1, Jincai He1, Kunlin Jin1,3,*, Bei Shao1,*
1Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research,
2Department of Clinical Laboratory Medicine, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 35000, China
3Institute for Healthy Aging, Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
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Interleukin-33 (IL-33), a newly recognized IL-1 family member, is expressed in various tissues and cells, and involved in pathogenesis of many human diseases. For example, IL-33 plays a protective role in cardiovascular diseases. However, the role of IL-33 in acute ischemic stroke (AIS) remains unclear. This study aims to investigate whether IL-33 level in AIS patient serum can be used as a potential diagnostic and prognostic marker. The study included two hundred and six patients with first-ever ischemic stroke, who were admitted within 72 hours after stroke onset. The serum level of IL-33 was measured with ELISA and the severity of AIS patients on admission was evaluated based on the National Institutes of Health Stroke Scale (NIHSS) score. The functional outcome at 3 months was determined using the Barthel index (BI). We found that serum IL-33 was significantly higher (P < 0.001) in patients with AIS [57.68 ng/L (IQR, 44.95-76.73)] compared with healthy controls [47.48 ng/L (IQR, 38.67-53.78)]. IL-33 was an independent diagnostic biomarker for AIS with an OR of 1.051 (95%Cl, 1.018-1.085; P=0.002). Serum IL-33 was higher (P < 0.05) in the stroke patients with small cerebral infarction volume compared to AIS patients with large cerebral infarction. In addition, serum IL-33 was also significantly higher (P = 0.001) in the patients with mild stroke, compared to the patients with severe stroke. Furthermore, serum IL-33 level in AIS patients with a worse outcome was higher (P < 0.001) compared to AIS patients with a better outcome. IL-33 was also an independent predictor for the functional outcome with an adjusted OR of 0.932 (95% CI, 0.882-0.986). Our results suggest that the lower level of serum IL-33 is associated with large infarction volume and greater stroke severity in AIS patients. Thus, IL-33 can be used as a novel and independent diagnostic and predicting prognostic marker in AIS.

Keywords interleukin-33      acute ischemic stroke      outcome      biomarker      diagnosis     
Corresponding Authors: Kunlin Jin,Bei Shao   
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These authors contributed equally to this work

Issue Date: 01 October 2016
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Qian Li
Yuanshao Lin
Wensi Huang
Yulei Zhou
Xiaoli Chen
Brian Wang
Wanli Zhang
Zhengyi Cai
Jie Xue
Wenhui Zhang
Tieer Yu
Hong Wang
Jincai He
Kunlin Jin
Bei Shao
Cite this article:   
Qian Li,Yuanshao Lin,Wensi Huang, et al. Serum IL-33 Is a Novel Diagnostic and Prognostic Biomarker in Acute Ischemic Stroke[J]. Aging and disease, 2016, 7(5): 614-622.
URL:     OR
Age (years), Median (IQR)63 (52-69)62 (52-67)64 (55-71)0.036
Sex (no.):< 0.001
Systolic blood pressure162 (147-178)160 (146-177)170 (149-186)0.096
Diastolic blood pressure84 (76-94)84 (76-94)86 (75-96)NS
Median NIHSS score (IQR)4 (2-7)3 (2-5)9 (7-11)< 0.001
Infarction volume (mL IQR n=175)1.27 (0.53-4.80)1.1 (0.40-3.41)5.10 (1.66-7.56)< 0.001
Risk factors (no)
 Diabetes mellitus4631130.035
 Atrial fibrillation221910.035
 Alcohol abuse56482< 0.001
Laboratory findings (median, IQR)
 WBC (109/L)6.58 (5.50-8.03)6.60 (5.46-7.99)6.37 (5.81-7.77)NS
 Lithic acid (μmol/L)285.00 (226.00-366.50)291.00 (234.00-369.00)257.00 (208.25-341.75)NS
 Vit D (nmol/L)57.31 (38.73-76.23)58.53 (39.67-78.61)51.73 (36.75-74.82)NS
 TC (mmol/L)*4.94 ± 1.054.93 ± 1.044.99 ± 1.03NS
 TG (mmol/L)1.57 (1.15-2.28)1.61 (1.21-2.42)1.56 (1.16-2.04)NS
 HDL (mmol/L)1.08 (0.94-1.29)1.06 (0.93-1.27)1.12 (1.00-1.32)NS
 LDL (mmol/L)*2.92 ± 0.862.90 ± 0.853.05 ± 0.88NS
 Glucose (mmol/L)4.90 (4.40-6.15)4.90 (4.40-5.83)5.30 (4.65-8.35)0.044
 IgG (mg/mL)12.00 (10.70-13.80)11.75 (10.60-13.80)13.15 (10.88-14.05)NS
 IgA (mg/mL)2.27 (1.71-3.13)2.20 (1.63-3.13)2.61 (2.22-3.26)0.019
 IgM (mg/mL)0.99 (0.78-1.38)0.97 (0.78-1.43)1.16 (0.76-1.54)NS
 Hs-CRP (mg/L)1.82 (0.70-3.99)1.79 (0.74-3.69)4.13 (2.20-8.06)< 0.001
 HbA1c (%)5.80 (5.50-7.10)5.80 (5.50-6.48)6.35 (5.80-8.13)0.013
 IL-33 (ng/L)57.68 (44.95-76.73)62.53 (47.19-81.34)49.83 (36.20-61.22)< 0.001
Table 1  Baseline characteristics of patients with favorable or unfavorable outcomes
Figure 1.  Serum levels of IL-33 in different groups. (A) Serum levels of IL-33 in IAS Patients and healthy controls. (B) Serum levels of IL-33 in small and large infarct volume groups. Statistical comparisons were made using the Mann-Whitney test. A: P < 0.001; B: P < 0.05.
PredictionAUC95% CIP
Glucose0.3320.269-0.394< 0.001
Lithic acid0.3520.282-0.423< 0.001
HDL0.2470.187-0.307< 0.001
HbA1c0.6560.588-0.724< 0.001
Hs-CRP0.6400.563-0.717= 0.001
IL-330.7060.645-0.767< 0.001
Table 2  Accuracy of serum biomarkers in stroke
GroupNMedian, ng/L (IQR)
Small infarct volume13459.36 (47.92-79.51)a, b
Large infarct volume4155.72 (39.24-67.23)c
Control8147.48 (38.67-53.78)
Table 3  Serum interleukin-33 levels in different infarction volume and control groups
GroupNMedian, ng/L (IQR)
Mild stroke group15360.32 (47.43-79.65)a,b
Severe stroke group5352.77 (37.45-64.16)c
Control8147.48 (38.67-53.78)
Table 4  Serum interleukin-33 levels in mild and severe stroke patients and healthy controls
Univariate AnalysisMultivariate Analysis

Sex0.2490.121-0.510< 0.0010.0420.004-0.5040.012
Systolic blood pressure1.0140.999-1.0300.075--
NIHSS score1.7761.503-2.099< 0.0012.6121.615-4.224< 0. 001
Atrial fibrillation6.1340.796-47.2420.082--
Diabetes mellitus0.6010.28-1.2920.193--
Alcohol abuse9.7962.272-42.2440.002--
WBC (*109/L)1.0930.929-1.2870.284-
Lithic acid (μmol/L)0.9970.993-1.0010.092--
Vit D (nmol/L)0.9900.977-1.0050.183--
TC (mmol/L)1.0510.758-1.4580.766--
TG (mmol/L)0.8510.641-1.1810.344--
HDL (mmol/L)1.0880.334-3.5490.888--
LDL (mmol/L)1.2210.824-1.8090.320--
IgG (mg/mL)1.0830.955-1.2290.214--
IgA (mg/mL)1.3911.046-1.8510.023--
IgM (mg/mL)1.1640.721-1.8770.534--
HbA1c (%)1.2631.043-1.5300.017--
Glucose (mmol/L)1.1331.010-1.2700.033--
Hs-CRP (mg/L)1.1631.066-1.2700.0011.5611.12-2.1770.009
IL-33(ng/L)0.9520.931-0.973< 0.0010.9320.882 -0.9860.006
Table 5  Univariate and multivariate logistic regression analysis for outcome
PredictionAUC95% CIP
NIHSS score0.1070.056-0.157< 0.001
Hs-CRP0.2900.197-0.382< 0.001
IL-330.7200.639-0.801< 0.001
Table 6  Prediction of clinic outcome
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