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. 2022 Dec;70(8):1720-1727.
doi: 10.1136/jim-2021-002134. Epub 2022 May 30.

Serum levels of IL-37 and correlation with inflammatory cytokines and clinical outcomes in patients with coronary artery disease

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Serum levels of IL-37 and correlation with inflammatory cytokines and clinical outcomes in patients with coronary artery disease

Ali Rafiei et al. J Investig Med. 2022 Dec.

Abstract

Coronary artery disease (CAD) due to atherosclerosis is one of the important reasons for death worldwide. Recent evidence has suggested the essential role of inflammation in the progression of atherosclerosis. Interleukin (IL)-37 is a critical anti-inflammatory member of the IL-1 family which regulates the inflammatory processes. The aim of this study was to compare the serum levels of IL-37 in patients with CAD compared with the control group and its correlation with oxidative stress, cholesterol homeostasis, and inflammation in patients with CAD. A total of 42 patients with CAD and 42 sex-matched and age- matched controls who underwent coronary angiography were included in this study. The serum levels of IL-37 were evaluated via ELISA. Serum levels of biochemical risk factors were determined by enzymatic methods. Serum levels of IL-37 in the CAD group subjects were significantly lower than in the control group and IL-37 was significantly increased in men with CAD than in women with CAD. IL-37 significantly had an inverse correlation with IL-6, tumor necrosis factor-α, IL-32, high-sensitivity C reactive protein, oxidized low-density lipoprotein, and malondialdehyde. Also, IL-37 had a significantly positive correlation with ferric-reducing antioxidant power (FRAP) assay. In addition, IL-37 has positively correlated with ATP-binding cassette transporter A1 and G1 gene expression in peripheral blood mononuclear cells and serum levels of the FRAP. A receiver operating characteristic test displayed that IL-37 level ratios were a relatively significant CAD predictor. Our results indicated that decreased serum levels of IL-37 in patients with CAD and its relationship with inflammatory cytokines and reverse cholesterol transport genes are more likely to be associated in the inflammatory process with disease pathology.

Keywords: coronary artery disease; cytokines; inflammation; interleukins; tumor necrosis factor-alpha.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
The comparison of serum levels of IL-37 between CAD and control groups and its level in groups with different grades of arterial stenosis. (A) Serum levels of IL-37 in the CAD group (76.7 pg/mL) was significantly lower than the control group (107.7 pg/mL) by −1.4-fold (p=0.0006). (B) Serum levels of IL-37 significantly differed between control and CS1 (FC=−1.37; p=0.022), control and CS2 (FC=−1.40; p=0.012), control and CS3 groups (FC=−1.42; p=0.010). However, no significant difference was detected between CS1, CS2, and CS3 groups. Parametric unpaired t-test was used to compare the IL-37 concentration between control and CAD groups. An ordinary one-way analysis of variance test was used to compare the IL-37 concentration between all groups. P value ≤0.05 was considered as a significant value. Results are expressed as the mean±SEM. CAD, coronary artery disease; CS, coronary stenosis; IL, interleukin.
Figure 2
Figure 2
Receiver operating characteristic (ROC) curves for prediction of CAD according to serum levels of IL-37, hs-CRP, and ox-LDL. (A) Area under curve (95% CI) for IL-37=0.721 (0.608 to 0.834), (p=0.0009). (B) Area under curve (95% CI) for hs-CRP=0.8116 (0.715 to 0.907), (p<0.0001). (C) Area under curve (95% CI) for ox-LDL=0.7486 (0.640 to 0.857), (p=0.0002). CAD, coronary artery disease; hs-CRP, high-sensitivity C reactive protein; IL, interleukin; ox-LDL, oxidized low-density lipoprotein.
Figure 3
Figure 3
The comparison of serum levels of IL-37 between CAD and control groups individually in men and women. (A) The serum levels of IL-37 were significantly increased in the men of the control group than in the men of the CAD group (FC=1.65). (B) The serum levels of IL-37 were significantly increased in the women of the control group than in the women of CAD group (FC=1.16). (C) The serum levels of IL-37 were significantly increased in men with CAD than in women with CAD group (FC=1.09). (D) Serum levels of IL-37 were significantly higher in men than women (FC=1.33). P value ≤0.05 was considered as a significant value. Results are expressed as the mean±SEM. CAD, coronary artery disease; IL, interleukin.
Figure 4
Figure 4
Correlation between serum levels of IL-37 with hs-CRP, ox-LDL, FRAP, and MDA in the patients with CAD. (A) Serum levels of IL-37 was negatively correlated with hs-CRP (r=−0.407; p=0.013). (B) Serum levels of IL-37 was negatively correlated with ox-LDL (r=−0.552; p=0.0003). (C) Serum levels of IL-37 was positively correlated with FRAP (r=0.392; p=0.014). (D) The negative correlation between serum levels of IL-37 and MDA was not significant (r=−0.442; p=0.005). P values ≤0.05 were considered as significant using Pearson’s rank correlation. CAD, coronary artery disease; FRAP, ferric-reducing antioxidant power assay; hs-CRP, high-sensitivity C reactive protein; IL, interleukin; MDA, malondialdehyde; ox-LDL, oxidized low-density lipoprotein.
Figure 5
Figure 5
Correlation between serum levels of IL-37 with IL-6, TNF-α, and IL-32 in the patients with CAD. (A) Serum levels of IL-37 was negatively correlated with IL-6 (r=−0.429; p=0.011). (B) Serum levels of IL-37 was negatively correlated with TNF-α (r=−0.386; p=0.021). (C) Serum levels of IL-37 was not correlated with IL-32 (r=−0.408; p=0.016). P values ≤0.05 were considered as significant using Pearson’s rank correlation. CAD, coronary artery disease; IL, interleukin; TNF-α, tumor necrosis factor-α.
Figure 6
Figure 6
Correlation of serum levels of IL-37 with ABCA1 and ABCG1 genes expression in PBMCs of the patients with CAD. Serum levels of IL-37 had a significant positive correlation with expression levels of ABCA1 (r=0.484; p=0.002) and ABCG1 (r=0.339; p=0.04) genes in PBMCs of patients with CAD. P values ≤0.05 were considered as significant using Pearson’s rank correlation. ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; CAD, coronary artery disease; IL, interleukin; PBMCs, peripheral blood mononuclear cells.

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