Monocytes are short-lived cells and undergo spontaneous apoptosis every day. Inflammatory responses may induce dramatic up-regulation of monocyte survival and differentiation. When monocytes are recruited to an area of infection they may differentiate into macrophages. In different microenvironments macrophages polarize into two types. The M1 or classically activated macrophages are characterized by the high ability to produce pro-inflammatory cytokines and the production of NO through the induced synthesis of iNOS. The M2 or alternatively activated macrophages are divided into 3 subtypes, M2 a, b and c, and they have anti-inflammatory properties. Mediators of M1 macrophage TLR-dependent polarization include transcription factors such as NF-κB, AP-1, PU.1, CCAAT/enhancer-binding protein α (C/EBP-α), STAT1 as well as interferon regulatory factor 5 (IRF5), while the transcription factors which promote M2 activation include IRF4, C/EBP-β, Krüppel-like factor 4 (KLF4), STAT6 and PPARγ receptor.

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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.

IL-6 is a pleiotropic cytokine involved in the regulation of the immune response, inflammation, and hematopoeisis. Its elevated levels are found in a range of autoimmune and chronic inflammatory diseases. IL-6 is also involved in regulation of the balance between two T cell subsets: Tregs and Th17, which have contradictory functions in the control of inflammation. The present study provides a quantitative analysis regarding the Th17/Treg cell balance in peripheral blood of children with type 1 diabetes and its association with serum IL-6 level.

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