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.