Increased Interleukin-35 suppresses peripheral CD14+ monocytes function in patients with Kawasaki disease

Abstract

Background: Interleukin-35 (IL-35) is a newly identified IL-12 cytokine family member, which regulates the activity of immune cells in infectious diseases and autoimmune disorders. However, the regulatory function of IL-35 in Kawasaki disease is not well elucidated. Methods: Thirty-three patients with Kawasaki disease and seventeen healthy controls were studied. Peripheral IL-35 concentration was measured by enzyme linked immunosorbent assay. CD14 + monocytes were purified, and mRNA expression of IL-35 receptor (IL-12Rβ2 and gp130) was semi-quantified by real-time polymerase chain reaction. CD14 + monocytes were stimulated with recombinant IL-35. The modulatory role of IL-35 treated CD14 + monocytes to naïve CD4 + T cell activation was investigated by flow cytometry. The influence of IL-35 to cytotoxicity of CD14 + monocytes was assessed by measuring target cell death, cytokine and granzyme secretion.Results: Plasma IL-35 concentration was elevated in patients with Kawasaki disease. There was no significant differences of either IL-12Rβ2 or gp130 mRNA expression in CD14 + monocytes between Kawasaki disease patients and controls. IL-35 suppressed CD14 + monocytes induced naïve CD4 + T cell activation in Kawasaki disease, and this process required direct cell-to-cell contact. IL-35 also inhibited tumor necrosis factor-α and granzyme B secretion by CD14 + monocytes from patients with Kawasaki disease, however, only granzyme B was responsible for the cytotoxicity of CD14 + monocytes.Conclusions: IL-35 played an important immunosuppressive role to CD14 + monocytes function in Kawasaki disease.

IL-35 Regulates the Function of Immune Cells in Tumor Microenvironment

“…Subsequently, Wang et al identified that numbers of i35-Bregs were remarkably increased with the accumulation of CD14 + monocytes (37). Moreover, IL-35 suppressed CD14 + monocytes induced naive CD4 + T cell activation and the production of TNF-a and granzyme B, inhibiting cytotoxicity of them, whereas this effect has not been reported in TME (87). Further studies are needed to elucidate that function of IL-35 in the complex role of endothelial cells and monocytes during the angiogenesis in the TME.…”

The Role of IL-35 in the Pathophysiological Processes of Liver Disease

“…Evidences showed that IL-35 expression was obviously elevated in HCV patients, and had a positive association with DNA and RNA load of virus ( Liu et al, 2017 ). Langhans et al have found that the viral core antigen could induce the production of specific Tregs in chronic viral infection patients ( Xing and Tian, 2020 ). Treg cells comprised 5% to 10% of CD4+ T cells.…”

“…Furthermore, circulating IL-35 expression level might suggest the dysfunctional immune system in anti-tumor response, showing the activation of Tregs and the apoptosis of CD8+ T cell ( Heim et al, 2019 ). Moreover, IL-35 expression level was positively correlated with intrahepatic cholangiocarcinoma (ICC) aggressiveness, and served as an independent prognostic factor ( Xing and Tian, 2020 ). IL-35R was composed by heterodimer of IL-12Rβ2 chain and gp130 chain or homodimers of each chain.…”

“…IL-35R was composed by heterodimer of IL-12Rβ2 chain and gp130 chain or homodimers of each chain. Luckily, it was noted that gp130 had a better accuracy to predict the survival and recurrence of ICC patient compared with the traditional TNM stage ( Xing and Tian, 2020 ). The expression of IL-35 or gp130 was an independent prognostic factor in IL-35-mediated ICC ( Zhang et al, 2018 ; Xing and Tian, 2020 ).…”

“…Luckily, it was noted that gp130 had a better accuracy to predict the survival and recurrence of ICC patient compared with the traditional TNM stage ( Xing and Tian, 2020 ). The expression of IL-35 or gp130 was an independent prognostic factor in IL-35-mediated ICC ( Zhang et al, 2018 ; Xing and Tian, 2020 ). Moreover, IL-35 was reported to promote the differentiation of pro-inflammatory liver MΦ, and accelerate the shift from M1 to M2, suggesting that IL-35 was a beneficial target to break immune tolerance and facilitate a functional cure of chronic viral infections ( Figure 3 ).…”