Abstract
Inflammation has received considerable attention in the pathogenesis of type 2 diabetes mellitus (T2DM). Supporting this concept, enhanced expression of interleukin (IL)-1β and increased infiltration of macrophages are observed in pancreatic islets of patients with T2DM. Although IL-1 receptor antagonist (IL-1Ra) plays a major role in controlling of IL-1β-mediated inflammation, its counteraction effects and epigenetic alterations in T2DM are less studied. Thus, we aimed to analyze the DNA methylation status in IL1RN, RELA (p65) and NFKB1 (p50) genes in peripheral blood mononuclear cells (PBMCs) from treated T2DM patients (n = 35) and age-/sex- matched healthy controls (n = 31). Production of IL-1β and IL-1Ra was analyzed in plasma and supernatants from LPS-induced PBMCs. Immunomodulatory effects of IL-1β and IL-1Ra were studied on THP-1 cells. Average DNA methylation level of IL1RN and NFKB1 gene promoters was significantly decreased in T2DM patients in comparison with healthy controls (P< 0.05), which was associated with the increased IL-1Ra (P< 0.001) and IL-1β (P = 0.039) plasma levels in T2DM patients. Negative association between average methylation of IL1RN gene and IL-1Ra plasma levels were observed in female T2DM patients. Methylation of NFKB1 gene was negatively correlated with IL-1Ra levels in the patients and positively with IL-1β levels in female patients. LPS-stimulated PBMCs from female patients failed to raise IL-1β production, while the cells from healthy females increased IL-1β production in comparison with unstimulated cells (P< 0.001). Taken together, the findings suggest that hypomethylation of IL1RN and NFKB1 gene promoters may promote the increased IL-1β/IL-1Ra production and regulate chronic inflammation in T2DM. Further studies are necessary to elucidate the causal direction of these associations and potential role of IL-1Ra in anti-inflammatory processes in treated patients with T2DM.
Highlights
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia, loss of insulin sensitivity and progressive dysfunction of pancreatic β cells [1]
To the best of our knowledge, the study provides the first evidence of hypomethylation of IL1RN and NFKB1 genes which may contribute to the immunologic landscape of type 2 diabetes mellitus (T2DM)
The balance between IL-1β and IL-1 receptor antagonist (IL-1Ra) is a major determinant of the time course and severity of inflammatory diseases
Summary
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia, loss of insulin sensitivity and progressive dysfunction of pancreatic β cells [1]. Multiple evidences support the presence of islet inflammation including observations of enhanced expression of pro-inflammatory interleukin (IL)-1β, various cytokines and chemokines, increased infiltration of CD68+ macrophages [3,4] which were shown to contribute to the local inflammation, insulin resistance and pancreatic dysfunction in T2DM [4,5]. IL-1β activity is regulated by an endogenous inhibitor IL-1 receptor antagonist (IL-1Ra) [8] Both members of IL-1 family binds with high affinity to specific IL-1 receptors type 1 (IL-1R1) leading to intracellular signal transduction and, as a result, cellular responses [9]. The fine-tuned balance between IL-1β and IL-1Ra at the IL-1R1 site is critical in determining responses in pancreatic β cells and to the progression of the diseases in general
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