Treatment with the PPARγ agonist rosiglitazone downregulates interleukin-1 receptor antagonist in individuals with metabolic syndrome

Objectives: Thiazolidinediones (TZDs) reduce insulin resistance, but also have pleiotropic properties including effects on inflammation. The balance between protective and proatherogenic effects may differ in various patient populations. We studied the effect of rosiglitazone on inflammatory markers in patients with metabolic syndrome (MetSyn). Methods: In a cross-over randomized controlled trial, 23 subjects with MetSyn were assigned to treatment with rosiglitazone that was uptitrated from 4 mg/day for 6 weeks followed by 8 mg/day for 6 weeks or matching placebo for 12 weeks, and then to the opposite treatment for 12 weeks. Plasma levels of inflammatory and metabolic markers were measured during follow-up. Results: Our main findings were i) compared to placebo, rosiglitazone significantly decreased the plasma levels of the naturally occurring interleukin (IL) 1 inhibitor, IL1 receptor antagonist (IL1Ra; P=0.001), potentially reflecting inflammatory effects on the IL1 system; ii) parallel to this, rosiglitazone decreased plasma levels of IL10 (P=0.029) further suggesting inflammatory effects; iii) rosiglitazone decreased uric acid levels (P=0.001), and monocyte chemoattractant protein-1 (P=0.05) and C-reactive protein (P=0.06) tended to be lower after rosiglitazone than placebo, suggesting potential pro-and anti-inflammatory effects simultaneously and iv) in vitro, rosiglitazone enhanced IL1Ra and decreased IL1 beta in THP-1 monocytes, illustrating the complex effects of these medications, potentially exhibiting anti-inflammatory effects on the IL1 system in certain tissues or cells at least at certain concentrations. Conclusion: Our findings suggest inflammatory effects on the IL1 system during rosiglitazone therapy in MetSyn. However, anti-inflammatory effects were also observed, and the net effect of TZDs in MetSyn should be further investigated.