Interleukin-1 receptor antagonist (IL-1ra) is a naturally occurring antagonist of IL-1α and IL-1β 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-γ-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-κB/PU.1 binding site plays an important role in this SB203580-mediated upregulation of IL-1ra. Considering that IFN-γ is a major stimulator of the innate and adaptive immune responses, the upregulation of anti-inflammatory IL-1ra expression by SB203580 in the IFN-γ-stimulated microglia might provide a new therapeutic modality for various inflammatory diseases of the central nervous system.
Bibliographical noteFunding Information:
This work was supported by Korea Research Foundation Grant KRF-2004-015-C00469 to H.S. Kim. J.S. Park was supported by Brain Korea 21 grant in 2006.
- IL-1 receptor antagonist
- Protein kinase B