SB203580 enhances interleukin-1 receptor antagonist gene expression in IFN-gamma-stimulated BV2 microglial cells through a composite nuclear factor-kappa B/PU.1 binding site

초록

Interleukin-1 receptor antagonist (IL-1ra) is a naturally occurring antagonist of IL-1 alpha and IL-1 beta binding to the IL-1 receptors and alleviates various inflammatory reactions. Therefore, the upregulation of IL-1ra expression is important for preventing and/or treating inflammatory diseases including many neurodegenerative diseases. This study found that SB203580, which is generally known as a p38 MAP kinase inhibitor and an anti-inflammatory agent, increased the level of IL-1ra expression in IFN-gamma-stimulated BV2 microglial cells. This effect is believed to occur through the inhibition of protein kinase B (PKB), independently of the p38 MAP kinase pathways. Further mechanistic studies using an IL-1ra promoter revealed that a composite NF-kappa B/PU.1 binding site plays an important role in this SB203580-mediated upregulation of IL-1ra. Considering that IFN-gamma is a major stimulator of the innate and adaptive immune responses, the upregulation of anti-inflammatory IL-1ra expression by SB203580 in the IFN-gamma-stimulated microglia might provide a new therapeutic modality for various inflammatory diseases of the central nervous system. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

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