Insulin Inhibits the Pro-Inflammatory Transcription Factor Early Growth Response Gene-1 (Egr)-1 Expression in Mononuclear Cells (MNC) and Reduces Plasma Tissue Factor (TF) and Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations

Ahmad Aljada, Husam Ghanim, Priya Mohanty, Neeti Kapur and Paresh Dandona

Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, Buffalo, New York 14209

Abstract

We have recently demonstrated that an infusion of a low dose of insulin reduces the intranuclear NF-{kappa}B (a pro-inflammatory transcription factor) content in MNC while also reducing the p;asma concentration of NF-{kappa}B dependent pro-inflammatory cytokines and adhesion molecules. We have now tested the effect of insulin on the pro-inflammatory transcription factor, early growth response-1 (Egr-1) and plasma concentration of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), two major proteins whose expression is modulated by Egr-1. Insulin was infused at the rate of 2 IU/h in 5% dextrose (100 mL/h) and KCI (8 mmol/h) for 4 h in the fasting state in ten obese subjects. Blood samples were obtained at 0, 2, 4 and 6 h. MNC were isolated and their total homogenates and nuclear fractions were prepared and Egr-1 was measured by electrophoretic mobility shift assay (EMSA). Plasma TF and PAI-1 were assayed by ELISA. There was a significant fall in Egr-1 at 2 (66 ± 14% of basal level) and 4 h (47 ± 17% of the basal level; P<0.01). PAI-1 levels (basal = 100%) decreased significantly after insulin infusion at 2 h (57 ± 6.7% of the basal level) and at 4 h (58 ± 8.3% of the basal level; P<0.001). Plasma TF levels (basal = 100%) decreased to 76 ± 7.7% of the basal level at 2 h and to 85 ± 10.4% of the basal level at 4 h (P<0.05). Thus, insulin reduces intranuclear Egr-1 and the expression of TF and PAI-1. These data provide further evidence that insulin has an anti-inflammatory effect including the inhibition of TF and PAI-1 expression. These effects suggest a potential beneficial effect of insulin in thrombin formation and fibrinolysis in atherothrombosis.