IL-10 and socs3 Are Predictive Biomarkers of Dengue Hemorrhagic Fever

Abstract

Background: Cytokines play important roles in the physiopathology of dengue infection; therefore, the suppressors of cytokine signaling (socs) that control the type and timing of cytokine functions could be involved in the origin of immune alterations in dengue.

Objective: To explore the association of cytokine and socs levels with disease severity in dengue patients.

Methods: Blood samples of 48 patients with confirmed dengue infection were analyzed. Amounts of interleukins IL-2, IL-4, IL-6, and IL-10, interferon- (IFN-) γ, and tumor necrosis factor- (TNF-) α were quantified by flow cytometry, and the relative expression of socs1 and socs3 mRNA was quantified by real-time RT-PCR.

Results: Increased levels of IL-10 and socs3 and lower expression of socs1 were found in patients with dengue hemorrhagic fever (DHF) with respect to those with dengue fever (DF) (p < 0.05). Negative correlations were found between socs1 and both IL-10 and socs3 (p < 0.01). The cutoff values of socs3 (>199.8-fold), socs1 (<1.94-fold), and IL-10 (>134 pg/ml) have the highest sensitivity and specificity to discriminate between DF and DHF.

Conclusion: Simultaneous changes in IL-10 and socs1/socs3 could be used as prognostic biomarkers of dengue severity.

Figure 1

Cytokine concentrations in patients with dengue. Cytokines were determined by cytometric bead array in the blood plasma of the healthy subjects, in all patients with dengue, in DF, and DHF. Results show the values of all subjects belonging to each group; error bars represent mean ± S.D. Significant differences ^∗P < 0.05; ^∗∗∗P < 0.001 by Mann–Whitney U test for continuous variables.

Figure 2

Relative expression of socs genes in patients with dengue. The relative expression of socs1 and socs3 mRNA was determined in PBMC of patients with DF and DHF. Results are expressed as fold increments compared with the expression level of the control group which was assigned an arbitrary value of 1. Error bars represent mean ± S.D. Significant differences ^∗P < 0.05; ^∗∗P < 0.01 by Mann–Whitney U test for continuous variables.

Figure 3

Correlation analysis between socs1, socs3, and IL-10. Spearman's and Pearson's correlation coefficients were calculated to identify the association between IL-10 concentration and socs1 expression (a) and between socs3 and socs1 expression levels (b).

Figure 4

Predictive analysis of immunological biomarkers to identify dengue severity. The ROC curves were plotted using the sensitivity and specificity data and the cutoff values presented in Table 3, with the software GraphPad Prism 5. soc3, socs1, IL-10, and albumin discriminate between DF and DHF.