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Molecular and Cellular Biology, March 2004, p. 2385-2396, Vol. 24, No. 6
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.6.2385-2396.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Interleukin-10 Inhibits Interleukin-12 p40 Gene Transcription by Targeting a Late Event in the Activation Pathway

Liang Zhou, Aaron A. Nazarian, and Stephen T. Smale*

Howard Hughes Medical Institute and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095-1662

Received 20 August 2003/ Returned for modification 12 September 2003/ Accepted 16 December 2003

Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that suppresses the induction of proinflammatory cytokine genes, including the IL-12 p40 gene. Despite considerable effort examining the effect of IL-10 on specific transcription factors and signaling molecules, the mechanism by which IL-10 inhibits gene transcription has remained elusive. To provide a different perspective to this problem, we examined the effect of IL-10 on molecular events occurring at the endogenous IL-12 p40 locus in lipopolysaccharide-stimulated peritoneal macrophages. IL-10 abolished recruitment of RNA polymerase II to the p40 promoter. However, it only modestly reduced binding of C/EBPß, as monitored by genomic footprinting and chromatin immunoprecipitation. It also had little effect on NF-{kappa}B complexes that are critical for p40 induction. A substantial reduction in nucleosome remodeling at the p40 promoter was observed, but the magnitude of this reduction appeared insufficient to account for the strong inhibition of transcription. Finally, a lipopolysaccharide-inducible DNase I hypersensitive site identified 10 kb upstream of the start site was unaffected by IL-10. Thus, despite a dramatic reduction in p40 transcription, several events required for activation of the endogenous p40 gene occurred relatively normally. These findings suggest that IL-10 blocks one or more events that occur after p40 locus decondensation and nucleosome remodeling and after, or in parallel with, the binding of a subset of p40 transcriptional activators.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, UCLA, 6-730 MRL, 675 Charles E. Young Dr. South, Los Angeles, CA 90095-1662. Phone: (310) 206-4777. Fax: (310) 206-8623. E-mail: smale{at}mednet.ucla.edu.

Molecular and Cellular Biology, March 2004, p. 2385-2396, Vol. 24, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.6.2385-2396.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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