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Nucleosome remodeling at the IL-12 p40 promoter is a TLR-dependent, Rel-independent event

Nature Immunology volume 2, pages 51–57 (2001)Cite this article

Abstract

Lipopolysaccharide (LPS) induction of the gene encoding interleukin 12 p40 requires remodeling of a promoter-encompassing nucleosome and the Toll-like receptor (TLR)–mediated activation of a c-Rel–containing complex. Analysis of TLR4-mutant mice revealed that remodeling requires TLR signaling. However, Rel proteins and other proteins required for transcription of an integrated p40 promoter were insufficient for remodeling. c-Rel was also unnecessary for remodeling, as remodeling was observed in c-Rel−/− macrophages, which lack p40 transcripts. These results suggest that remodeling requires TLR signaling pathways that diverge from the c-Rel activation pathways. The factors that stimulate remodeling may represent, therefore, newly identified targets of TLR signaling and of agents that regulate inflammatory responses and TH1 development.

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Figure 1: Restriction enzyme accessibility versus ChIP as a measure of nucleosome remodeling.
Figure 2: Nucleosome remodeling at the p40 promoter is a TLR-dependent event.
Figure 3: Comparison of endogenous and stably integrated IL-12 p40 promoters.
Figure 4: Comparison of restriction enzyme accessibility at the endogenous and stably integrated p40 promoters.
Figure 5: Remodeling at the p40 promoter in Rel−/− macrophages.

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Acknowledgements

We thank S. Plevy for providing the RAW264.7 cell lines containing the stably integrated p40 promoter-CAT reporter plasmids, V. Schuman, S. Sea and J. Park for maintaining mouse colonies and D. Baltimore, D. Thanos and R. Modlin for helpful discussions and critical reading of the manuscript. Supported by US Public Health Service grants GM07185 (to A. S. W. and M. N. B.) and AI07323 (to S. S.) and a University of California Dissertation-Year Fellowship (to A. S. W.). S. T. S. is an Investigator with the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Microbiology Immunology and Molecular Genetics, UCLA, Los Angeles, 90095-1662, CA, USA

    Amy S. Weinmann, Deborah M. Mitchell, Shomyseh Sanjabi, Michelle N. Bradley & Stephen T. Smale

  2. Department of Biology, California Institute of Technology, Pasadena, 91125, CA, USA

    Alexander Hoffmann

  3. Division of Immunology, Department of Medicine, Cornell University Medical College, New York, 10021 , NY, USA

    Hsiou-Chi Liou

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  1. Amy S. Weinmann
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Correspondence to Stephen T. Smale.

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Weinmann, A., Mitchell, D., Sanjabi, S. et al. Nucleosome remodeling at the IL-12 p40 promoter is a TLR-dependent, Rel-independent event. Nat Immunol 2, 51–57 (2001). https://doi.org/10.1038/83168

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