Reference - Detail
| RRC ID | 36852 |
|---|---|
| Author | Hiroi M, Sakaeda Y, Yamaguchi H, Ohmori Y. |
| Title | Anti-inflammatory cytokine interleukin-4 inhibits inducible nitric oxide synthase gene expression in the mouse macrophage cell line RAW264.7 through the repression of octamer-dependent transcription. |
| Journal | Mediators Inflamm |
| Abstract |
Inducible nitric oxide synthase (iNOS) is a signature molecule involved in the classical activation of M1 macrophages and is induced by the Nos2 gene upon stimulation with Th1-cell derived interferon-gamma (IFNγ) and bacterial lipopolysaccharide (LPS). Although the anti-inflammatory cytokine IL-4 is known to inhibit Nos2 gene expression, the molecular mechanism involved in the negative regulation of Nos2 by IL-4 remains to be fully elucidated. In the present study, we investigated the mechanism of IL-4-mediated Nos2 transcriptional repression in the mouse macrophage-like cell line RAW264.7. Signal transducer and activator of transcription 6 (Stat6) knockdown by siRNA abolished the IL-4-mediated inhibition of Nos2 induced by IFNγ/LPS. Transient transfection of a luciferase reporter gene containing the 5'-flanking region of the Nos2 gene demonstrated that an octamer transcription factor (OCT) binding site in the promoter region is required for both positive regulation by IFNγ/LPS and negative regulation by IL-4. Although IL-4 had no inhibitory effect on the DNA-binding activity of constitutively expressed Oct-1, IL-4-induced Nos2-reporter transcriptional repression was partially attenuated by overexpression of the coactivator CREB-binding protein (CBP). These results suggest that a coactivator/cofactor that functionally interacts with Oct-1 is a molecular target for the IL-4-mediated inhibition of Nos2 and that IL-4-activated Stat6 represses Oct-1-dependent transcription by competing with this coactivator/cofactor. |
| Volume | 2013 |
| Pages | 369693 |
| Published | 2013-1-1 |
| DOI | 10.1155/2013/369693 |
| PMID | 24459328 |
| PMC | PMC3891534 |
| MeSH | Animals Cells, Cultured Interferon-gamma / pharmacology Interleukin-4 / pharmacology* Lipopolysaccharides / pharmacology Macrophages / enzymology Membrane Proteins / physiology Mice Nitric Oxide Synthase Type II / antagonists & inhibitors Nitric Oxide Synthase Type II / genetics* Octamer Transcription Factor-1 / physiology* Organic Cation Transport Proteins Organic Cation Transporter 2 Phosphoproteins / physiology Promoter Regions, Genetic STAT6 Transcription Factor / physiology |
| IF | 3.758 |
| Times Cited | 15 |
| Resource | |
| Human and Animal Cells | BCL1-B20(RCB2618) |