Abstract
Both increased serum ferritin levels and Toll-like receptor (TLR) activation show independent association with the inflammatory processes. During inflammation, cell activation and apoptosis are accompanied by the release of membrane-derived microparticles (MPs), which are considered to be mediators of intercellular communication as they induce specific responses in target cells. The aim of this study was to determine whether glycated and glycoxidated ferritin induce in vitro release TLR microparticles from CD14+ peripheral blood mononuclear cells. Peripheral blood mononuclear cells were stimulated with glycated, glycoxidated and native ferritin. The release of microparticles from CD14+ cells, the presence of TLR2+ and TLR4+ on the microparticles surface and the presence of interleukins-6 and -8 (IL-6 and IL-8) inside the microparticles after stimulation were determined by flow cytometry. The role of nuclear factor ?B (NF-?B) was evaluated by pretreatment of the cells with the Bay 11-7085 inhibitor. Glycated and glycoxidated ferritin induced the release of microparticles from CD14+ cells, the majority of which expressed TLR2+ and TLR4+ on their surface and contained IL-6 and IL-8. These effects were dependent on NF-?B activation. Our findings show that glycated and glycoxidated ferritin might be involved in the release of microparticles and stimulation of inflammatory responses.
Highlights
Increased levels of serum ferritin and inflammatory markers such as tumor necrosis factor alpha (TNFα) and C-reactive protein (CRP) are frequently related to systemic inflammatory diseases [1,2,3,4]
The percentage of MPs derived from CD14+ was significantly increased from the basal control when cells were stimulated with 50 ng/mL Gly-ferritin or 50 ng/mL GlyOx-ferritin
Glycated and glycoxidated ferritin increases the expression of TLR2 and TLR4 in CD14+ microparticles
Summary
Increased levels of serum ferritin and inflammatory markers such as tumor necrosis factor alpha (TNFα) and C-reactive protein (CRP) are frequently related to systemic inflammatory diseases [1,2,3,4]. In patients with diabetes mellitus this leads to an increased risk of atherosclerosis, a risk factor for vascular complications in diabetes [7]. TLR2 and TLR4 bind to components of Gram-positive and Gram-negative bacteria, respectively, but they are activated by endogenous ligands, including hyaluronic acid fragments, necrotic cells, serum amyloid A, advanced glycation end-products (AGEs) and extracellular matrix components. TLR2 and TLR4 may play important roles in inflammatory disorders, including atherosclerosis and diabetes mellitus, as shown by the increased expression of TLR2 and TLR4 in monocytic cells under hyperglycemic conditions and in macrophages from human atherosclerotic
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