SB203580 enhances interleukin-1 receptor antagonist gene expression in IFN-gamma-stimulated BV2 microglial cells through a composite nuclear factor-kappaB/PU.1 binding site.
Interleukin-1 receptor antagonist (IL-1ra) is a naturally occurring antagonist of IL-1alpha and IL-1beta 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-kappaB/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.
Park
Jin-Sun
JS
Department of Neuroscience and Medical Research Institute, College of Medicine, Ewha Womans University, Seoul, South Korea.
Jung
Soo-Hyun
SH
Seo
Hyemyung
H
Kim
Hee-Sun
HS
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D017628:Microglia; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D004791:Enzyme Inhibitors; D007093:Imidazoles; D007371:Interferon-gamma; D053590:Interleukin 1 Receptor Antagonist Protein; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D012333:RNA, Messenger; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; D000099232:Proto-Oncogene Protein Spi-1; C507764:Il1rn protein, mouse; C093642:SB 203580