Rosiglitazone as a Regulator of Innate Immunity in a Cell Model of Hyperglycemia

摘要

Epidemiological studies have shown that severe inflammatory responses occur in patients with hyperglycemia. The molecular nature of these changes is currently under intense investigations. A central role of nuclear receptors PPAR has been shown in the regulation of metabolic changes associated with hyperglycemia, a selective agonist of nuclear receptor PPARy rosiglitazone is used as a hypoglycemic drug. Rosiglita-zone is known to have anti-inflammatory effects, but its properties as an anti-inflammatory drug in hyperglycemic conditions have not been studied. This was an aim of our work. We used a human cell culture model of hyperglycemia: He La cells incubated in the conditions of 25 mM glucose for 3 days. Control cells were incubated with 5 mM glucose. The cells were stimulated with lipopolysaccharide (LPS) that is known to trigger innate immune response through activation of Toll-like receptor 4 and influence mRNA expression levels. of three of PPAR (a, β/δ, γ) isotypes as well as cyclooxygenase (COX-1 and COX-2). We have shown that under hyperglycemic conditions expression levels of PPARa and PPARβ/δ decreased almost twofold, expression level of COX-2 also decreased, while expression levels of COX-1 and PPARy remained unchanged compared to those under normal glucose concentration. LPS administration in control cells leads to a 1.5-2.5-fold stimulation of expression of COX-2 and PPAR isotypes. In contrast, under hyperglycemia, LPS exhibited no effect on expression of COX-2 and the PPAR isotypes, which indicates potential mechanisms of hyperglycemia-related alterations fn innate immunity. Rosiglitazone, an agonist of PPARy, decreased expression level of PPARp/δ and abolished the effect of LPS under hyperglycemia. Rosiglitazone also reduced expression level of COX-1 and COX-2, which indicates on the agonist possible role as an anti-inflammatory agent under high glucose concentrations. These data broaden applicability of rosiglitazone as an anti-inflam-matory agent in hyperglycemic conditions.