IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages

Smallie, Tim, Ricchetti, Giuseppe, Horwood, Nicole J ORCID: https://orcid.org/0000-0002-6344-1677, Feldmann, Marc, Clark, Andrew R and Williams, Lynn M (2010) IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages. Journal of Experimental Medicine, 207 (10). pp. 2081-2088. ISSN 0022-1007

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	genetics,genetics,cells, cultured,genetics,humans,genetics,immunology,pharmacology,immunology,nf-kappab inhibitor alpha,genetics,promoter regions, genetic,genetics,genetics,drug effects,transcriptional activation,genetics
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	06 Mar 2019 12:30
Last Modified:	25 Sep 2024 13:57
URI:	https://ueaeprints.uea.ac.uk/id/eprint/70162
DOI:	10.1084/jem.20100414

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