Abstract 10237: Interleukin-1 Receptor-associated Kinase 3 (IRAK3) is a Potential Monocyte-related Link between Inflammation and Oxidative Stress in Obesity and Atherosclerosis
Background: Low-grade inflammation and oxidative stress synergize in the development of obesity, type 2 diabetes and cardiovascular diseases. Previously, we identified in activated blood monocytes of obese women a cluster of molecules linking the induction of the inflammatory toll-like receptor 2 / tumor necrosis factor alpha (TLR2/TNFα) pathway with the decrease of antioxidant defense by superoxide dismutase 1 (SOD1) and catalase (CAT). IRAK3 was the only inhibitor of the inflammatory pathway that was inversely related to BMI, inflammation and oxidized LDL.
Objectives: The aim of this study was to identify the molecular mechanisms determining the role of IRAK3 in inflammation and oxidative stress in vitro and in mice.
Methods & Results: siRNA silencing of IRAK3 (n = 10, P <0.0001) in human monocytic THP-1 cells increased TNFα (P <0.001), measured by qRT-PCR, and reactive oxygen species (ROS) production (P <0.05), determined by flow cytometry. In IRAK3-depleted cells, exposure to ROS (induced by glucose oxidase) resulted in increased inflammation and oxidative stress characterized by a profound induction of TNFα and ROS, and a decrease in SOD1 and CAT (all P <0.001). Exposure to high glucose or oxidized LDL (at concentrations measured in obese persons), which increases ROS, resulted in a decrease in IRAK3 (P <0.05 and P <0.01). Furthermore, the anti-inflammatory and antioxidative action of adiponectin was nullified when IRAK3 expression was depleted. In addition, we measured Irak3 in mice with combined leptin and LDL-receptor deficiency (DKO) that are obese and have dyslipidemia, hyperglycemia and insulin resistance and hypertension. In 24-week-old DKO mice (n = 26), atherosclerotic plaque macrophages expressed less Irak3 (P <0.05), and rosiglitazone treatment (n = 13) increased it. Less Irak3 was associated with more Tnfα (P <0.05), less Sod1 and Cat (P <0.001), and more oxidized LDL (P <0.01).
Conclusions: Depletion of IRAK3 in monocytes results in increased inflammation associated with elevated ROS. Decreased antioxidant defense associated with higher ROS and oxidized LDL results in depletion of IRAK3. Thus, IRAK3 is a potential link in the vicious circle between inflammation and oxidative stress in obesity and associated atherosclerosis.
- © 2010 by American Heart Association, Inc.