Abstract

Background: Cytokines can be key factors in the pathogenesis of coronary artery disease (CAD). This systematic review and meta-analysis aimed to assess the levels of interleukin-10 (IL-10), an anti-inflammatory cytokine, in the serum/plasma of patients with CAD.


Methods: An exhaustive search was conducted across the Web of Science, PubMed/Medline, Scopus, and Cochrane Library databases up to March 25, 2022. Review Manager 5.3 software was used to calculate the effect sizes, presenting the standardized mean difference (SMD) along with a 95% confidence interval (CI). STRING software, which maps protein-protein interactions (PPI), was utilized to explore the functional interactions among the genes under study.


Results: From the 1130 records retrieved from the databases, 26 articles were included in the meta-analysis. The pooled SMD for CAD cases compared to controls was 0.33 (p = 0.15). The sample size was adequate for comparing blood IL-10 levels in CAD patients versus controls.


Conclusion: The findings suggest there was no significant difference in the serum/plasma levels of IL-10 between CAD patients and controls. Hence, the pathogenesis of CAD can be multifactorial and complex.

Keywords: heart disease interleukin-10 serum plasma meta-analysis


Introduction

Heart diseases (HDs) are the leading cause of death worldwide, with the majority of fatalities, approximately 80%, occurring in low- to middle-income countries. If current trends continue, it is projected that by 2030, cardiovascular diseases will claim the lives of about 23.6 million individuals, predominantly through heart attacks and strokes1, 2. Ischemic HD is recognized as a significant threat in the 21st century3, also known as coronary artery disease (CAD) or coronary HD. A large number of individuals with CAD live with chronic disabilities and impaired quality of life4.

One of the most significant risk factors associated with HD is a family history of HD5. The increase in HD risk due to family history can be attributed to shared genetic, environmental, and lifestyle factors. The importance of genetics becomes more apparent with the early onset of HD in the family and the number of family members affected6. It is believed that an imbalance between pro- and anti-inflammatory activities plays a crucial role in the development of atherosclerosis7. Inflammation contributes to the early stages of HD, and therefore, may drive the progression of this disease8, 9.

CAD is the primary cause of deaths related to cardiovascular issues10, and atherosclerosis is the most common reason for CAD, which is a longstanding inflammatory condition of the arterial walls that arises from an inappropriate inflammatory response and an imbalance in lipid metabolism11. A multitude of evidence, including both clinical trials and experimental studies, collectively indicates that inflammation is integral to all phases of atherosclerosis development9, 12, 13.

Several signaling pathways have been reported and linked to CAD pathogenesis14, 15, 16, 17. Cytokines, which are part of the extracellular signaling proteins, are secreted by both immune and non-immune cells, including cells of the vascular endothelium18. Increased levels of inflammatory cytokines in the plasma have been documented in patients with CAD, especially in those with unstable disease conditions10. Conversely, the presence of anti-inflammatory mediators is less well documented. Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that plays a vital and often indispensable role in warding off inflammatory and autoimmune conditions19, 20, 21, 22. The gene for human IL-10 is located on chromosome 1, specifically at the juncture of regions 1q31 and 1q3223. IL-10 can reduce the likelihood of atherosclerosis development and improve the progression of atherosclerosis and vascular complications24. Studies have documented the role of plasma/serum IL-10 levels in CAD patients but with varying and contradictory results25, 26, 27. The interactions of IL-10 are complex and can vary depending on the specific context and conditions28, 29, 30.

To our knowledge, this topic has not been the subject of a meta-analysis. Therefore, the goal of this meta-analysis was to assess the levels of IL-10 in the blood of patients with CAD to obtain better and more accurate results and to identify the possible reasons for these discrepancies between the results of individual studies. Another aim was to understand the pathogenesis, protein-protein interactions (PPI), and patient-specific factors as research gaps.

Methods

Design and Registration

This study adhered to the guidelines set forth by PRISMA31. Additionally, the protocol for this meta-analysis was registered in the PROSPERO database under the registration number CRD42022335594. The question posed in terms of PECO was: Is there an association between serum/plasma levels of IL-10 and the risk of CAD in studies with a case-control design?

Article Discovery

An author of the study, M.S., carried out a comprehensive search in databases such as PubMed/MEDLINE, Web of Science, Scopus, and Cochrane Library up until March 25, 2022, without imposing any restrictions, to collect relevant articles. M.S. also reviewed the titles and abstracts of these articles. Subsequently, the full texts of the articles that met the selection criteria were obtained. The search strategy included keywords/title/abstract: ("coronary atherosclerotic heart disease" or "coronary heart disease" or "coronary artery disease" or "ischemic heart disease" or "myocardial infarction" or "acute coronary syndrome" or "angina pectoris") and ("interleukin-10" or "IL-10" or "IL10" or "interleukin 10") and ("plasma" or "serum" or "blood") and ("control" or "normal" or "healthy"). The bibliographies of the retrieved articles were scrutinized to ensure no significant studies were missed. Another author, R.H.M., verified the search and selection procedures. In the event of any discrepancies between the two authors, a third author, N.S., intervened in the resolution.

Criteria for Selection and Rejection

The inclusion criteria were as follows: 1) Any study that reported the levels of IL-10 in the serum or plasma of CAD patients and control subjects. 2) Studies that included more than 10 cases in both the case and control groups. 3) CAD was defined based on the criteria reported in Alshammary's study32, and Table 1 shows the criteria for each study. 4) CAD patients without any other systemic diseases and control subjects who were in good health. 5) CAD patients with or without medical treatment, such as statins. Conversely, review articles, meta-analyses, articles with missing data, studies conducted on animals, articles lacking a control group, commentary papers, conference papers, book chapters, duplicate studies, studies that included disease-afflicted controls, and studies involving cases under treatment were excluded.

Table 1.

Definition of CAD used in each study included in the analysis

First author, publication year CAD definition
Mazzone, 1999 33 Standard progressive changes in electrocardiography linked with a rise in CK values exceeding twice the upper normal limit and alterations in the ST-segment
Mizia-Stec, 2002 34 Coronangiography
Mizia-Stec, 2003 35 Coronangiography was performed if there was a constriction of the diameter by 75% or more in at least one of the three primary epicardial coronary arteries
Lee, 2006 36 Cardiac catheterization
Nilsson, 2006 37 Angiography
Szodoray, 2006 38 Angiography
Paulsson, 2008 39 Angiography
Cheng, 2009 40 Scanning with radioactive thallium or coronary angiogram
Jha, 2009 41 Angiography
Jha, 2010 42 Angiography
Khan, 2011 43 Angiography revealing a stenosis of more than 70% in at least one coronary vessel
Tapp, 2012 44 European Society of Cardiology definition
Karu, 2013 45 NR
Li, 2015 46 Clinical symptoms, ECG alterations, coronary angiography, and cardiac troponin tests
Mirhafez, 2015 47 Angiography
Cheng, 2016 48 Coronary stenosis with at least one main coronary vessel with 50% luminal narrowing
Liang, 2016 49 A narrowing of the lumen by 50% or more was observed in at least one primary coronary artery or its main branches
Bergström, 2017 25 Non-segment elevation myocardial infarction identified through characteristic ECG alterations and increased levels of troponins
Tajfard, 2017 50 An occlusion of 50% or more in at least one coronary artery
Xu, 2017 51 Stenosis exceeding 50% in at least one primary vessel
Boles, 2018 26 Angiography
Kharaeva, 2018 27 Angiography
Kumari, 2018 18 NR
Ansari, 2019 52 Angiography revealing stenosis exceeding 70% in a single coronary artery
Shipulin, 2020 53 Left ventricular ejection fraction ≤ 40%, stenosis left main or proximal part of the left descending artery or two or more epicedial vessels ≥ 75%
Nowrouzi-Sohrabi, 2022 54 Angiography confirmed stenosis of more than 50% in at least one coronary artery

Data Summary

The authors, M.S. and M.R., independently extracted data from the studies included in the meta-analysis. Extracted data encompassed authors' names, publication year, study country, case ethnicity, the number of coronary artery disease (CAD) patients and control subjects, sample size, average age, IL-10 levels in serum or plasma, and the quality score.

Quality Evaluation

The quality assessment was conducted by one author, M.S., using the Newcastle-Ottawa Scale (NOS) tool to evaluate the quality and potential bias in case-control studies55. The highest possible score on the NOS is nine, with scores of seven or higher indicative of high quality.

Statistical Analyses

The Review Manager 5.3 (RevMan 5.3, The Cochrane Collaboration, Oxford, UK) software was utilized to calculate effect sizes, providing the standardized mean difference (SMD) and a 95% confidence interval (CI) for IL-10 levels in the blood of CAD cases and controls. The Z-test determined the significance of the pooled SMD, considering a two-sided p-value of less than 0.05 significant. If heterogeneity was significant, indicated by a Pheterogeneity value of less than 0.1 and an I2 value greater than 50%, a random-effects model56 was used. Conversely, a fixed-effect model57 wad used in cases of insignificant heterogeneity.

Subgroup analysis, random meta-regression analysis, and sensitivity analysis ("one-study-removed" and "cumulative" analyses) were performed using the Comprehensive Meta-Analysis version 2.0 (CMA 2.0; Biostat Inc., Englewood, NJ, USA). Publication bias was assessed using Egger's58 and Begg’s tests59, with a 2-sided p < 0.10 indicating the presence of publication bias.

The NCSS 2021 version 21.0.2 (NCSS, Kaysville, UT, USA) software generated two plots (Radial and L'Abbé plots). The Radial, or Galbraith, plot displays the z-statistic60, and the L’Abbé plot illustrates event rates in cases compared to control groups61, 62, with a p-value less than 0.05 indicating statistically significant heterogeneity.

Trial Sequential Analysis (TSA) was conducted using TSA software (version 0.9.5.10 beta) (Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark)63. The required information size (RIS) was calculated with an alpha risk of 5%, a beta risk of 20%, and a two-sided boundary type. The studies were considered to have included sufficient cases if the Z-curve intersected the RIS line, adhered to the boundary line, or entered the futility area. Otherwise, additional information and further studies were deemed necessary.

Functional interactions between examined genes were studied using the STRING software, a protein-protein interaction network tool accessed at https://string-db.org/ (accessed on 5 August 2023)64. Interaction settings were limited to "Homo sapiens" and required an interaction score threshold of more than 0.900. In the resulting networks, proteins are represented by nodes, and interactions are indicated by edges. STRING was used to identify potential interactions between differentially expressed genes (DEGs) in various tissues, with KEGG analysis obtained from the STRING software.

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Figure 1 . Flowchart of the study choice .

Results

Choice of Studies

After removing duplicates and records that were not relevant, 63 out of the 1130 records that were initially retrieved from the databases met the criteria for inclusion as full-text articles (Figure 1). Subsequently, 37 full texts were removed for reasons. At last, 26 articles including 27 studies were entered into the meta-analysis.

Attributes of the Study

The main features of 26 articles18, 25, 26, 27, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 incorporated in the meta-analysis are shown in Table 2. The articles were disseminated from 1999 to 2022. Seventeen articles25, 26, 27, 33, 34, 35, 37, 38, 39, 43, 44, 45, 47, 50, 51, 52, 53, 54 were reported in Caucasians and nine18, 36, 40, 41, 42, 46, 48, 49, 51 in Asians. Eleven articles25, 26, 33, 37, 41, 42, 44, 46, 51, 53, 54 were reported IL-10 level in plasma and fifteen18, 27, 34, 35, 36, 38, 39, 40, 43, 45, 47, 48, 49, 50, 52 in serum. Other variables and the quality score of each article are shown in Table 2 and Table 3, respectively. A few studies in some cases reported the CAD patients under statin therapy.

Table 2.

Traits of the studies incorporated in the meta-analysis

First author, publication year Country Ethnicity Sample Groups Number Mean age, years IL-10 level (Mean ± SD) Detection assay
Mazzone, 1999 33 Italy Caucasian Plasma CAD 42 61 10.8 ± 1.8 ELISA
CO 39 55 1.9 ± 1.1
Mizia-Stec, 2002 34 Poland Caucasian Serum CAD 100 58.0 52.37 ± 106.15 ELISA
CO 20 55.3 14.3 ± 28.5
Mizia-Stec, 2003 35 Poland Caucasian Serum CAD 33 60.9 68.0 ± 152.5 ELISA
CO 20 55.4 14.3 ± 28.5
Lee, 2006 36 Taiwan Asian Serum CAD 30 65.5 1.56 ± 1.37 ELISA
CO 73 63 1.22 ± 0.85
Nilsson, 2006 37 Sweden Caucasian Plasma CAD 65 56.9 2.58 ± 2.04 ELISA
CO 28 52.5 2.4 ± 2.5
Szodoray, 2006 38 Hungary Caucasian Serum CAD 62 64.2 32.3 ± 95.3 ELISA
CO 58 72.3 6.95 ± 15.38
Paulsson, 2008 39 Sweden Caucasian Serum CAD 19 61 0.73 ± 0.67 Immunoassay
CO 19 60 0.55 ± 0.49
Cheng, 2009 40 Taiwan Asian Serum CAD 138 65.5 2.1 ± 0.2 ELISA
CO 74 63 1.2 ± 0.1
Jha, 2009 41 India Asian Plasma CAD 192 - 1.83 ± 0.16 ELISA
CO 192 - 1.95 ± 0.19
Jha, 2010 42 India Asian Plasma CAD (male) 148 - 1.83 ± 0.15 ELISA
CAD (female) 42 - 1.82 ± 0.16
CO (male) 142 - 1.94 ± 0.17
CO (female) 50 - 1.94 ± 0.18
Khan, 2011 43 Pakistan Caucasian Serum CAD 98 40 2.07 ± 1.70 ELISA
CO 74 35 1.7 ± 1.85
Tapp, 2012 44 UK Caucasian Plasma CAD 40 60.4 0.55 ± 0.93 Flow cytometry
CO 40 59.5 0.88 ± 1.16
Karu, 2013 45 Estonia Caucasian Serum CAD 39 64 0.53 ± 0.19 High-sensitivity array
CO 39 62 0.65 ± 0.21
Li, 2015 46 China Asian Plasma CAD 29 66.9 18.74 ± 20.84 ELISA
CO 11 62.3 20.92 ± 14.69
Mirhafez, 2015 47 Iran Caucasian Serum CAD 289 59.1 0.75 ± 0.29 Sandwich Chemiluminescence
CO 89 58.7 0.84 ± 0.39
Cheng, 2016 48 China Asian Serum CAD 52 60 7.42 ± 3.81 ELISA
CO 50 59 17.46 ± 5.01
Liang, 2016 49 China Asian Serum CAD 128 65.3 134.43 ± 38.24 ELISA
CO 106 64.7 164.38 ± 36.45
Bergström, 2017 25 Sweden Caucasian Plasma CAD 57 66 0.32 ± 0.12 ELISA
CO 41 67 1.03 ± 0.13
Tajfard, 2017 50 Iran Caucasian Serum CAD 231 59.5 0.76 ± 0.29 Biochip array
CO 120 53.3 0.83 ± 0.34
Xu, 2017 51 China Asian Plasma CAD 264 59 98.65 ± 34.79 ELISA
CO 186 58 32.18 ± 12.15
Boles, 2018 26 Sweden Caucasian Plasma CAD 69 64.5 0.29 ± 0.21 ELISA
CO 140 58.6 0.25 ± 0.15
Kharaeva, 2018 27 Russia Caucasian Serum CAD 27 57 53.6 ± 3.2 ELISA
CO 20 55 10.0 ± 3.0
Kumari, 2018 18 India Asian Serum CAD 290 51.6 5.33 ± 3.34 ELISA
CO 290 51.7 5.83 ± 2.63
Ansari, 2019 52 Pakistan Caucasian Serum CAD 340 42 0.83 ± 0.53 ELISA
CO 310 39 0.87 ± 0.36
Shipulin, 2020 53 Russia Caucasian Plasma CAD 26 59.2 25.16 ± 4.07 ELISA
CO 14 58.6 20.5 ± 4.44
Nowrouzi-Sohrabi, 2022 54 Iran Caucasian Plasma CAD 15 58.9 1.98 ± 0.73 ELISA
CO 15 56.2 1.87 ± 0.92

Table 3.

Newcastle - Ottawa Scale for studies

First author, publication year Selection # Comparability & Exposure $ Total score
Mazzone, 1999 33 *** * ** 6
Mizia-Stec, 2002 34 **** ** ** 8
Mizia-Stec, 2003 35 **** ** ** 8
Lee, 2006 36 **** ** ** 8
Nilsson, 2006 37 **** ** ** 8
Szodoray, 2006 38 **** ** ** 8
Paulsson, 2008 39 **** ** ** 8
Cheng, 2009 40 **** ** ** 8
Jha, 2009 41 **** ** ** 8
Jha, 2010 42 **** ** ** 8
Khan, 2011 43 *** ** ** 7
Tapp, 2012 44 **** ** ** 8
Karu, 2013 45 **** ** ** 8
Li, 2015 46 **** ** ** 8
Mirhafez, 2015 47 **** ** ** 8
Cheng, 2016 48 **** ** ** 8
Liang, 2016 49 **** ** ** 8
Bergström, 2017 25 **** ** ** 8
Tajfard, 2017 50 **** ** ** 8
Xu, 2017 51 **** ** ** 8
Boles, 2018 26 *** ** ** 7
Kharaeva, 2018 27 **** ** ** 8
Kumari, 2018 18 **** ** ** 8
Ansari, 2019 52 *** ** ** 7
Shipulin, 2020 53 **** ** ** 8
Nowrouzi-Sohrabi, 2022 54 *** ** ** 7

Quality Score

The quality scores for case-control studies incorporated in the meta-analysis are shown in Table 3. Most studies involved a high quality (total score ≥ 7).

Pooled Analysis for All Studies

As Figure 2 shows, the pooled SMD for 85 studies reporting CAD patients was 0.33 (95%CI: ˗ 0.12, 0.78; p = 0.15; I2 = 98%). Based on the result, the two groups (patients with CAD and controls) did not exhibit a significant difference in blood IL-10 levels.

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Figure 2 . Forest plot analysis of blood interleukin-10 level in patients with coronary artery disease compared to controls.

Subgroup analysis

The subgroup analysis derived from ethnicity, blood sample, and sample size is shown in Table 4. The findings reported that sample size could be an effective factor in the pooled result.

Table 4.

Subgroup analysis

Variable Number of studies SMD 95%CI p-value Heterogeneity, %
Ethnicity
Caucasian 18 0.30 ˗ 0.16, 0.76 0.20 96
Asian 9 ˗ 0.29 ˗ 1.07, 0.49 0.46 99
Sample
Serum 15 0.42 ˗ 0.08, 0.93 0.10 97
Plasma 12 0.12 ˗ 0.77, 1.01 0.78 99
Sample size
≥200 11 0.93 0.24, 1.63 0.008 99
<200 16 ˗ 0.08 ˗ 0.72, 0.56 0.81 96

Sensitivity Analysis

The results of "one-study-removed" and "cumulative" analyses indicated that the combined analysis was stable.

Publication Bias

Figure 3 indicates funnel plots of blood IL-10 levels in controls compared to CAD patients. With regards to blood IL-10 levels, the p-values of tests were Egger’s: 0.274 and Begg’s: 0.128 for the CAD patients compared to controls. Publication bias was not observed.

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Figure 3 . Funnel plot analysis of blood interleukin-10 level coronary artery disease patients compared to controls .

Trial Sequential Analysis

Figure 4 presents the outcome of the TSA for blood IL-10 levels in CAD patients versus controls. The data indicates that there are ample cases for comparing blood IL-10 levels in CAD patients and controls.

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Figure 4 . Trial sequential analysis of blood interleukin-10 level in coronary artery disease patients compared to controls (D2 = 100%) .

Radial and L'Abbé plots

The results of both radial and L'Abbé plots for blood IL-10 levels in the CAD patients versus the controls are identified in Figure 5 and Figure 6, respectively. The radial plot indicated that one possible cause of heterogeneity in the initial analysis could be outliers. Also, the L'Abbé plot shows evidence of high heterogeneity (p < 0.001).

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Figure 5 . Radial plot of studies on blood IL-10 levels for patients with coronary artery disease versus controls .

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Figure 6 . L'Abbé plot of studies on plasma/serum interleukin-10 (IL-10) levels for patients with coronary artery disease versus controls . In the plot, each circle stands for a separate study, with the size of the circles being proportional to the weight of the study, which is determined by the number of participants. The diagonal line signifies that, within the studies, the average IL-10 levels were the same in both groups.

Meta-regression

Table 5 represents the random-effects meta-regression of IL-10 levels for CAD patients compared to controls. The results indicated that the publication year and blood sample were moderator factors in the pooled initial analyses (p < 0.01).

Table 5.

Random meta-regression of IL-10 levels for patients with coronary artery disease versus controls

Variable Data
Publication year Point Estimate ˗ 0.00065
SE 0.00020
Lower Limit ˗ 0.00103
Upper Limit ˗ 0.00026
Z ˗ 3.30123
0.00096
Sample Size Point Estimate 0.00023
SE 0.00016
Lower Limit ˗ 0.00008
Upper Limit 0.00053
Z 1.45301
0.14622
Blood sample Point Estimate ˗ 0.26738
SE 0.06390
Lower Limit ˗ 0.39263
Upper Limit ˗ 0.14214
Z ˗ 4.18444
0.00003

IL-10/STAT3/SOCS3 axis and PPI interaction

Figure 7 shows the IL-10/STAT3 pathway and its role in suppressing inflammation. IL-10 activates STAT3, and the IL-10/STAT3 axis can have a powerful anti-inflammatory property65 and its role can be crucial in limiting undesirable immune reactions. It is possible that this axis could play a role in regulating inflammation in the context of CAD17. SOCS3 plays a role in the mechanism by which IL-10 modulates inflammation and acts as a feedback inhibitor of the JAK/STAT pathway. Further research would be needed to determine the exact role of the IL-10/STAT3/SOCS3 axis in CAD. The STRING PPI interaction contains 5 nodes with 10 edges with the highest confidence (0.900). The average node degree was 4 and the PPI enrichment p-value was 6.73e-5. In addition, the KEGG suggested a network analysis for the JAK-STAT signaling pathway based on 5 nodes entered into STRING (Figure 8).

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Figure 7 . IL-10/STAT3/SOCS3 axis in coronary artery disease (left) and PPI interaction between mentioned proteins in the axis .

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Figure 8 . KEGG analysis of JAK-STAT signaling pathway .

Discussion

Coronary artery disease (CAD), a prevalent cardiovascular condition, is characterized by the buildup of plaque within the coronary artery walls, leading to reduced blood flow to the heart muscle66. Our main findings showed no difference in the blood levels of IL-10 between the CAD patients and the controls. The analyses reported that factors such as ethnicity, blood sample type (serum or plasma), sample size, and publication year could affect the pooled results.

Limited knowledge exists regarding the function of anti-inflammatory cytokines in CAD. IL-10, an anti-inflammatory cytokine that effectively inhibits immune responses, is produced by T and B cells, monocytes, and macrophages67. It suppresses pro-inflammatory cytokines and has a broad range of anti-inflammatory capabilities, including the inhibition of early pro-inflammatory transcription factors, which consequently reduces cytokine production68.

In vitro, IL-10 plays a crucial role in diminishing lesion growth and preventing the advancement of atherosclerosis69, 70, as well as in modulating the immune response to atherosclerosis, a major contributor to CAD71. However, in clinical settings, the role of IL-10 in patients with CAD has yielded inconsistent results25, 26, 33, despite numerous studies investigating the relationship between IL-10 and CAD25, 27, 40.

One study suggested that CAD patients of both sexes who smoked and consumed alcohol had lower levels of IL-1042, while another demonstrated that CAD patients with low serum iron had significantly higher levels of IL-10 compared to normal controls or CAD patients with normal/high serum iron36. The current meta-analysis suggested that factors such as ethnicity, blood sample, sample size, and publication year could significantly influence the pooled results. Therefore, CAD progression and development may be influenced by several factors, and future studies should examine the effect of each factor individually to identify the most significant influences. According to one study, there was no significant correlation between serum IL-10 levels in CAD patients and factors such as smoking, hypertension, diabetes, obesity, and dyslipidemia72. The findings suggest that certain risk factors for CAD, such as dietary habits (e.g., low intake of fruits and vegetables, high intake of saturated fats), smoking, physical inactivity, and obesity, may reduce IL-10 levels and increase inflammation in the body73, 74, 75, 76, thus contributing to the disease's development. Understanding the underlying mechanisms of these associations may assist in identifying new preventive and therapeutic strategies for CAD.

IL-10 has been shown to suppress the generation of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and IL-1β, which are key contributors to the formation of atherosclerotic plaques68, 77. Additionally, IL-10 has been found to promote the survival of endothelial cells that line the inner surfaces of blood vessels and prevent their apoptosis, thereby reducing the risk of plaque formation78, 79.

Various studies have indicated that increased IL-10 levels in the bloodstream could signal ongoing systemic inflammation in CAD patients27, 33, 40, while other studies noted that in human coronary disease, IL-10 is present and associated with diminished signs of inflammation71, 80. The available evidence suggests that IL-10 plays a protective role against CAD by modulating the inflammatory response and promoting endothelial cell survival. Nonetheless, additional studies are needed to fully comprehend the mechanisms underlying the relationship between IL-10 and CAD.

Research has established that CAD is associated with a continuous inflammatory response81. STAT3 has been identified as a crucial molecule in IL-10's operation, with its activation necessary for the cytokine's anti-inflammatory effects82, 83. Furthermore, evidence suggests that SOCS3 plays a role in how IL-10 modulates inflammation17, 84. Acting as a feedback inhibitor of the JAK/STAT pathway, SOCS3 is crucial in preventing STAT3 activation, cytokine signaling, and the expression of inflammatory genes in immune cells such as macrophages and microglia85. One study found that IL-10 increased SOCS3 expression in cultured cardiomyocytes17. With regards to protein-protein interactions between IL-10, STAT3, and SOCS3, evidence supports that both STAT3 and SOCS3 are involved in IL-10's regulation of inflammation. Additionally, the KEGG analysis reported several biomarkers.

The effects of statins on IL-10 levels in CAD patients versus controls have varied across studies39. One trial reported that statin therapy did not affect IL-10 mRNA expression in patients with CAD86, while another study confirmed this for serum IL-10 levels87. Our meta-analysis included a few studies that involved cases with statin therapy; thus, we were unable to analyze data related to the effect of statins on IL-10 levels comprehensively. Future research should investigate the impact of statins on IL-10 levels in CAD patients. The meta-regression identified the publication year as a confounding factor in the pooled result, indicating possible significant differences in the therapeutic approach to CAD patients over time.

The significant limitations of this meta-analysis include heterogeneity among the studies, limited case count in some analyses, and the lack of patient-level data; diverse criteria for study inclusion, such as varying definitions of CAD, which could introduce bias; different patient populations; and varying methodologies. Additionally, the study mentions factors such as statin therapy that could influence IL-10 levels in CAD patients, but these confounding variables were not fully explored in the analysis. The quality assessment of the included studies was conducted by a single author, which may introduce subjective bias. A more systematic and independent quality assessment process could enhance the reliability of the results. While no evidence of publication bias was found, it is possible that studies with significant results may have been more likely to be published, leading to an over representation of certain findings in the meta-analysis. However, the strengths of the meta-analysis include the absence of publication bias, the high quality of most included studies, and the consistency of the combined results.

Conclusions

According to this systematic review and meta-analysis, no significant difference was observed in blood IL-10 levels between CAD patients and controls, suggesting that IL-10 may not serve as a reliable biomarker for CAD. The analysis included a sufficient number of cases for robust comparison, highlighting the complex and multifactorial nature of CAD. Further research is needed to better understand the role of inflammation and specific inflammatory markers in the development of CAD. Future studies should include larger sample sizes and explore the interaction of IL-10 with other proteins to enhance our understanding of CAD's pathogenesis and identify potential therapeutic targets. This study underscores the importance of continued research efforts to improve our comprehension of the mechanisms and risk factors involved in CAD.

This meta-analysis is clinically significant as it informs clinicians and researchers that IL-10 levels may not be useful for diagnosing or predicting CAD. It highlights the complex and multifactorial nature of CAD, indicating that many factors, not just IL-10, contribute to the disease's development. This insight is vital for clinicians when diagnosing and treating CAD.

Abbreviations

CAD - Coronary Artery Disease, CI - Confidence Interval, CK - Creatine Kinase, CO - Control, DEGs - Differentially Expressed Genes, ECG - Electrocardiographic/Electrocardiography, HDs - Heart Diseases, IL-10 - Interleukin-10, JAK - Janus Kinase, KEGG - Kyoto Encyclopedia of Genes and Genomes, NR - Not Reported, NOS - Newcastle-Ottawa Scale, PECO - Population, Exposure, Comparator, Outcome, PPI - Protein-Protein Interactions, PRISMA - Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PROSPERO - International Prospective Register of Systematic Reviews, RIS - Required Information Size, SD - Standard Deviation, SE - Standard Error, SMD - Standardized Mean Difference, SOCS3 - Suppressor of Cytokine Signaling 3, STAT3 - Signal Transducer and Activator of Transcription 3, TNF-α - Tumor Necrosis Factor-Alpha, TSA - Trial Sequential Analysis

Acknowledgments

None.

Author’s contributions

Conceptualization, R.H.M.; methodology, M.S.; software, M.S.; validation, R.H.M., and N.S.; formal analysis, M.S.; investigation, M.R. and M.S.; resources, M.S.; data curation, M.S.; writing—original draft preparation, N.S.; writing—review and editing, M.R. and M.S.; visualization, R.H.M.; supervision, N.S.; project administration, R.H.M.; funding acquisition, N.S. All authors have read and agreed to the published version of the manuscript.

Funding

None.

Availability of data and materials

Data and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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