Elevated Levels of Serum IL-12 and IL-18 are Associated with Lower Frequencies of CD4+CD25highFOXP3+ Regulatory T cells in Young Patients with Type 1 Diabetes

Abstract

Type 1 diabetes is thought to involve chronic inflammation, which is manifested by the activation and expression of different inflammatory mediators. IL-12 and IL-18 are two cytokines that have been shown to exert strong proinflammatory activity and have been implicated in the pathogenesis of type 1 diabetes in mice and humans. The overproduction of proinflammatory mediators is controlled by specialized T cell subset, namely regulatory T cells that express FOXP3 transcription factor. Since IL-12 and IL-18 mediate inflammatory response and Tregs exhibit anti-inflammatory potential, we aimed to examine their reciprocal relationship in patients with type 1 diabetes. The study group consisted of 47 children diagnosed with type 1 diabetes and 28 healthy individuals. Serum levels of IL-12 and IL-18 were measured by ELISA, and the peripheral blood CD4+CD25high FOXP3+ regulatory T cell frequencies were analyzed by flow cytometry. Patients with type 1 diabetes had a decreased percentage of circulating CD4+CD25highFOXP3+ Tregs in comparison to their healthy counterparts. In addition, they produced more IL-12 and IL-18 than children from the control group. Concentrations of these cytokines positively correlated with one another, as well as with CRP and HbA1c. Moreover, the negative association between IL-12, IL-18, CRP serum levels, and the frequency of regulatory CD4+CD25highFOXP3+ Tregs was observed. IL-12 and IL-18 may have direct or indirect impact on regulatory T cell subset, which may contribute to their reduced frequency in peripheral blood of patients with type 1 diabetes mellitus.

Increased expression of IL-18 in the serum and islets of type 1 diabetics

“…We performed ELISA assays on the plasma from these populations to analyze IL-18 levels. Confirming previous reports in adults and children [14, 26], we found that IL-18 is significantly increased in the sera of juvenile T1Ds compared to controls (p=0.0391; Figure 1A). Importantly, to determine if outliers were skewing the data toward a significant result, we also performed a ROUT test (Q=0.5%), to remove outliers.…”

“…Corroborating other reports [14, 24-26], we show a significant increase in the concentration of IL-18 in the serum of T1D patients compared to the control group. We also analyzed IL-18BP and IL-37 levels in these patients.…”

“…Additionally, our group has reported that IL-18 secretion is necessary for expansion of self-reactive T cells in NOD mice [21]. In humans, increased IL-18 levels have been observed in the serum of patients at high risk for developing T1D and type 2 diabetes (T2D) [22, 23], as well as in children and adults diagnosed with T1D and T2D[14, 24-27] [14, 24-27]. IL-18 protein expression was also observed within the pancreatic islets of patients with fulminant type 1 diabetes [28], and a significant association between elevated IL-18 serum levels and an increase in the number of autoantibodies detected was reported in new-onset type 1 diabetics (T1Ds) [29].…”

Interleukin-12: Functional activities and implications for disease

“…Interestingly, IL-12 levels were negatively correlated with the size of the Treg population [72]. Moreover, human beta cells were identified as an important target of IL-12 in T1D and IL-12-induced beta cell dysfunction, namely reduced insulin secretion in response to glucose stimulation, could be observed [73].…”

Cyclosporine restores hematopoietic function by compensating for decreased Tregs in patients with pure red cell aplasia and acquired aplastic anemia

“…The ratios are shown (f). *P < 0.05; **P < 0.01; ***P < 0.001 d i a b e t e s , a n d p s o r i a s i s a n d h a v e f o u n d t h a t CD4 + CD25 + FoxP3 + Treg numbers were profoundly decreased in patients with active disease [19][20][21][22][23]. Previous studies on bone marrow failure syndromes revealed a decrease in the CD4…”