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. 2023 Dec 20;13(5):102-114.
doi: 10.5493/wjem.v13.i5.102.

Altered expression of miR-125a and dysregulated cytokines in systemic lupus erythematosus: Unveiling diagnostic and prognostic markers

Tagreed Qassim Alsbihawi  1 , Mojtaba Zare Ebrahimabad  2 , Fakhri Sadat Seyedhosseini  3 , Homa Davoodi  4 , Nafiseh Abdolahi  5 , Alireza Nazari  6 , Saeed Mohammadi  7 , Yaghoub Yazdani  3
Affiliations

Altered expression of miR-125a and dysregulated cytokines in systemic lupus erythematosus: Unveiling diagnostic and prognostic markers

Tagreed Qassim Alsbihawi et al. World J Exp Med. .

Abstract

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder impacting multiple organs, influenced by genetic factors, especially those related to the immune system. However, there is a need for new biomarkers in SLE. MicroRNA-125a (miR-125a) levels are decreased in T cells, B cells, and dendritic cells of SLE patients. MiR-125a plays a regulatory role in controlling the levels of tumor necrosis factor-alpha (TNF-α) and interleukin 12 (IL-12), which are crucial pro-inflammatory cytokines in SLE pathogenesis.

Aim: To assess the levels of miR-125a, IL-12, and TNF-α in SLE patients' plasma, evaluating their diagnostic and prognostic value.

Methods: The study included 100 healthy individuals, 50 newly diagnosed (ND), and 50 SLE patients undergoing treatment. The patients were monitored for a duration of 24 wk to observe and record instances of relapses. MiR-125a expression was measured using real-time reverse transcription polymerase chain reaction, while ELISA kits were used to assess IL-12 and TNF-α production.

Results: The results showed significantly reduced miR-125a expression in SLE patients compared to healthy individuals, with the lowest levels in ND patients. TNF-α and IL-12 expression levels were significantly elevated in SLE patients, especially in the early stages of the disease. Receiver operating characteristic curve analyses, and Cox-Mantel Log-rank tests indicated miR-125a, TNF-α, and IL-12 as proper diagnostic biomarkers for SLE. A negative correlation was found between plasma miR-125a expression and IL-12/TNF-α levels in SLE patients.

Conclusion: Decreased miR-125a levels may be involved in the development of SLE, while elevated levels of IL-12 and TNF-α contribute to immune dysregulation. These findings offer new diagnostic and prognostic markers for SLE. Moreover, the negative correlation observed suggests an interaction between miR-125a, TNF-α, and IL-12. Further research is necessary to uncover the underlying mechanisms that govern these relationships.

Keywords: Biomarker; Interleukin-12; Systemic lupus erythematosus; Tumor necrosis factor alpha; microRNA-125a.

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Conflict of interest statement

Conflict-of-interest statement: All the authors declare that there are no conflicts of interest to disclose.

Figures

Figure 1
Figure 1
The expression levels of microRNA-125a, tumor necrosis factor-alpha, and interleukin 12 in systemic lupus erythematosus patients and normal subjects. This study examined the expression levels of microRNA-125a (miR-125a), tumor necrosis factor-alpha (TNF-α), and interleukin 12 (IL-12) in systemic lupus erythematosus (SLE) patients and normal subjects. A: The findings revealed that miR-125a expression was significantly lower in SLE patients compared to normal subjects; B: With the lowest levels observed in newly diagnosed patients; C: TNF-α expression was higher in SLE patients compared to normal subjects; D: Its levels were highest in newly diagnosed patients; E: Similarly, the expression of IL-12 was significantly elevated in SLE patients compared to normal subjects; F: It was highest in newly diagnosed patients. The Independent Samples t-test or Mann-Whitney U test were employed for comparing two groups, while one-way ANOVA with Tukey’s post-test or Kruskal-Wallis with Dunn-Bonferroni post-test were used for comparing more than two groups. The error bars represent means ± SD. Significance levels are denoted as bP < 0.01 and cP < 0.0001. HS: Humic subjects; PAT: Patients; UT: Under-treatment; ND: Newly diagnosed.
Figure 2
Figure 2
Diagnostic utilities of microRNA-125a, tumor necrosis factor-alpha, and interleukin 12 in systemic lupus erythematosus patients. Receiver operating characteristic curve analysis was performed to assess the diagnostic accuracy of microRNA-125a (miR-125a), tumor necrosis factor-alpha (TNF-α), and interleukin 12 (IL-12) in distinguishing systemic lupus erythematosus (SLE) patients from normal subjects and newly diagnosed SLE patients from those under treatment. A: The area under the curve (AUC) values for miR-125a were 0.8370 (95%CI: 0.7803 to 0.8936; P < 0.0001) in SLE patients vs normal subjects; B: 0.8102 (95%CI: 0.7279 to 0.8925; P < 0.0001) in newly diagnosed vs under treatment SLE patients; C: For TNF-α, the AUC values were 0.9668 (95%CI: 0.9476 to 0.9860; P < 0.0001) in SLE patients vs normal subjects; D: 0.9748 (95%CI: 0.9513 to 0.9983; P < 0.0001) in newly diagnosed vs. under treatment SLE patients; E: Regarding IL-12, the AUC values were 0.9778 (95%CI: 0.9599 to 0.9957; P < 0.0001) in SLE patients vs normal subjects; F: 0.9600 (95%CI: 0.9289 to 0.9911; P < 0.0001) in newly diagnosed vs under treatment SLE patients. HS: Humic subjects; PAT: Patients; UT: Under-treatment; ND: Newly diagnosed.
Figure 3
Figure 3
The correlations of microRNA-125a with tumor necrosis factor-alpha and tumor necrosis factor-alpha. A: The relationship between plasma levels of microRNA-125a (miR-125a) and interleukin 12 was assessed, revealing a significant negative correlation (r = -0.569, P < 0.0001) as demonstrated by Pearson correlation analysis; B: Similarly, the plasma levels of miR-125a and tumor necrosis factor-alpha showed a significant negative correlation (r = -0.570, P < 0.0001) based on the Pearson correlation study.
Figure 4
Figure 4
The prognostic utilities of microRNA-125a, tumor necrosis factor-alpha, and interleukin 12 to predict flare in systemic lupus erythematosus patients. Based on the optimal cut-off points obtained from receiver operating characteristic curve analyses, the levels of microRNA-125a (miR-125a), tumor necrosis factor-alpha (TNF-α), and interleukin 12 (IL-12) were categorized as low or high. The predictive ability of these biomarkers for the outcome (Flare) in systemic lupus erythematosus (SLE) patients was assessed using the log-rank test. A: The results showed that miR-125a was not significantly predictive of the outcome (P < 0.7151); B: TNF-α showed a potential for predicting the outcome, but the association was not statistically significant (P = 0.4828); C: In contrast, IL-12 demonstrated a significant predictive capability for the outcome in SLE patients (P = 0.0508) based on the log-rank test results.
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