Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

IL-10 plays a central nonredundant role in limiting inflammation in vivo. However, the mechanisms involved remain to be resolved. Using primary human macrophages, we found that IL-10 inhibits selected inflammatory genes, primarily at a level of transcription. At the TNF gene, this occurs not through an inhibition of RNA polymerase II (Pol II) recruitment and transcription initiation but through a mechanism targeting the stimulation of transcription elongation by cyclin-dependent kinase (CDK) 9. We demonstrated an unanticipated requirement for a region downstream of the TNF 3' untranslated region (UTR) that contains the nuclear factor κB (NF-κB) binding motif (κB4) both for induction of transcription by lipopolysaccharide (LPS) and its inhibition by IL-10. IL-10 not only inhibits the recruitment of RelA to regions containing κB sites at the TNF gene but also to those found at other LPS-induced genes. We show that although IL-10 elicits a general block in RelA recruitment to its genomic targets, the gene-specific nature of IL-10's actions are defined through the differential recruitment of CDK9 and the control of transcription elongation. At TNF, but not NFKBIA, the consequence of RelA recruitment inhibition is a loss of CDK9 recruitment, preventing the stimulation of transcription elongation.

Original publication

DOI

10.1084/jem.20100414

Type

Journal

J Exp Med

Publication Date

27/09/2010

Volume

207

Pages

2081 - 2088

Keywords

3' Untranslated Regions, Binding Sites, Cells, Cultured, Cyclin-Dependent Kinase 9, Humans, I-kappa B Proteins, Interleukin-10, Lipopolysaccharides, Macrophages, NF-KappaB Inhibitor alpha, NF-kappa B, Promoter Regions, Genetic, RNA Polymerase II, Transcription Factor RelA, Transcription, Genetic, Transcriptional Activation, Tumor Necrosis Factor-alpha