The regulation of EN-RAGE (S100A12) gene expression in human THP-1 macrophages


      EN-RAGE is a ligand for the receptor for advanced glycation end products (RAGE) and may be involved in the development of diabetic macro- and micro-angiopathy. This study is designed to investigate the regulation of EN-RAGE gene expression in human macrophages. The amounts of EN-RAGE mRNA were measured in cultured human THP-1 macrophages after treatment with various stimuli known to modulate atherosclerosis. First, interleukin-6 (IL-6), a proinflammatory cytokine, increased the level of EN-RAGE mRNA by ∼2-fold in a time- and a dose-dependent fashion. EN-RAGE protein was detected in the cultured medium and increased significantly by the addition of IL-6. The induction was abolished by pretreatment with the JAK kinase inhibitor and cycloheximide, but not with the MEK kinase inhibitor. Second, pioglitazone (PIO), a thiazolidinedione, decreased the level of EN-RAGE mRNA by ∼25% of the basal in a time- and a dose-dependent fashion. Pioglitazone also inhibited the induction of EN-RAGE mRNA by IL-6. These results indicate the production of EN-RAGE is induced by IL-6 through de novo protein synthesis via the JAK-STAT kinase pathway and inhibited by the activation of peroxisome proliferator-activated receptor-γ (PPARγ) in human macrophages.


      AGE (advanced glycation end product), RAGE (the receptor for advanced glycation end products), EN-RAGE (extracellular newly identified RAGE-binding protein), NF-κB (nuclear factor-κB), JAK (Janus kinase), STAT (signal transducer and activator of transcription protein), VCAM-1 (vascular cell adhesion molecule-1), ICAM-1 (intercellular cell adhesion molecule-1), IL-6 (interleukin-6), TNF-α (tumor necrosis factor-α), MCP-1 (monocyte chemoattractant protein-1), PPAR (peroxisome proliferator-activated receptor)


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