Dynamic and Transient Remodeling of the Macrophage IL-10 Promoter during Transcription
Open accessAbstract
To gain insight into the molecular mechanism(s) whereby macrophages produce large amounts of IL-10, we analyzed IL-10 gene expression and temporally correlated it with modifications to chromatin associated with the IL-10 promoter. In resting cells, which make essentially no cytokines, the IL-10 promoter is associated with histones containing little or no detectable modifications. Macrophages stimulated in the presence of immune complexes begin to produce high levels of IL-10 pre-mRNA transcripts within minutes of stimulation. Coincident with this transcription was a rapid and dynamic phosphorylation of histone H3 at specific sites in the IL-10 promoter. Histone phosphorylation was closely followed by the binding of transcription factors to the IL-10 promoter. Blocking the activation of ERK prevented histone phosphorylation and transcription factor binding to the IL-10 promoter. In contrast to histone phosphorylation, the peak of histone acetylation at this promoter did not occur until after transcription had peaked. Inhibition of histone deactylase did not alter IL-10 gene expression, suggesting that phosphorylation but not acetylation was the proximal event responsible for IL-10 transcription. Our findings reveal a rapid and well-orchestrated series of events in which ERK activation causes a rapid and transient phosphorylation of histone H3 at specific regions of the IL-10 promoter, resulting in a transient exposure of the IL-10 promoter to the transcription factors that bind there. This exposure is essential for the efficient induction of IL-10 gene expression in macrophages. To our knowledge, this represents a unique way in which the expression of a cytokine gene is regulated in macrophages.
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In macrophages, more acetylation of the Il10 promoter has been associated with enhanced transcription activity.
“Similarly, in macrophages, more acetylation of the Il10 promoter has been associated with enhanced transcription activity17.”
From The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance (2009) · cites this paper as [17]
Cites
Signaling to Chromatin through Histone Modifications
Cheung, P., Allis, C. D., & Sassone-Corsi, P. (2000) · Cell · doi:10.1016/s0092-8674(00)00118-5 · Cited by 989 · see citing works
Regulatory T cells and mechanisms of immune system control
O’Garra, A., & Vieira, P. (2004) · Nature Medicine · doi:10.1038/nm0804-801 · Cited by 809 · see citing works
p38-dependent marking of inflammatory genes for increased NF-κB recruitment
Saccani, S., Pantano, S., & Natoli, G. (2001) · Nature Immunology · doi:10.1038/ni748 · Cited by 694 · see citing works
Nowak, S. J., & Corces, V. G. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.02.007 · Cited by 622 · see citing works
Mediator and the mechanism of transcriptional activation
Kornberg, R. D. (2005) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2005.03.011 · Cited by 595 · see citing works
Pathogen recognition with Toll-like receptors
Kawai, T., & Akira, S. (2005) · Current Opinion in Immunology · doi:10.1016/j.coi.2005.02.007 · Cited by 576 · see citing works
TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes
Avni, O., Lee, D. H., Macián, F., Szabo, S. J., Glimcher, L. H., & Rao, A. (2002) · Nature Immunology · doi:10.1038/ni808 · Cited by 521 · see citing works
The role of IL-10 in promoting disease progression in Leishmaniasis
Kane, M. M., & Mosser, D. M. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.2.1141 · Cited by 514 · see citing works
Self-citationThomson, S., Clayton, A. L., Hazzalin, C. A., Rose, S., Barratt, M. J., & Mahadevan, L. C. (1999) · The EMBO Journal · doi:10.1093/emboj/18.17.4779 · Cited by 451 · see citing works
Reversal of Proinflammatory Responses by Ligating the Macrophage Fcγ Receptor Type I
Sutterwala, F. S., Noel, G. J., Salgame, P. R., & Mosser, D. M. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.1.217 · Cited by 327 · see citing works
Self-citationLee, D. U., Agarwal, S., & Rao, A. (2002) · Immunity · doi:10.1016/s1074-7613(02)00314-x · Cited by 323 · see citing works
New insights into the molecular mechanism of interleukin-10-mediated immunosuppression
Grütz, G. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0904484 · Cited by 296 · see citing works
The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain
Donnelly, R. P., Sheikh, F., Kotenko, S. V., & Dickensheets, H. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0204117 · Cited by 289 · see citing works
Brightbill, H. D., Plevy, S. E., Modlin, R. L., & Smale, S. T. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.4.1940 · Cited by 267 · see citing works
Removal of Promoter Nucleosomes by Disassembly Rather Than Sliding In Vivo
Boeger, H., Griesenbeck, J., Strattan, J. S., & Kornberg, R. D. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.05.013 · Cited by 258 · see citing works
CYTOKINES AND ANTICYTOKINES IN THE PATHOGENESIS OF SEPSIS
van der Poll, T., & van Deventer, S. V. (1999) · Infectious Disease Clinics of North America · doi:10.1016/s0891-5520(05)70083-0 · Cited by 240 · see citing works
The Dynamics of Chromatin Remodeling at Promoters
Mellor, J. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.06.023 · Cited by 221 · see citing works
Lucas, M., Zhang, X., Prasanna, V., & Mosser, D. M. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.1.469 · Cited by 197 · see citing works
Self-citationMAP kinase‐mediated phosphoacetylation of histone H3 and inducible gene regulation
Clayton, A. L., & Mahadevan, L. C. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00451-4 · Cited by 189 · see citing works
Th2-Specific Chromatin Remodeling and Enhancer Activity in the Th2 Cytokine Locus Control Region
Fields, P. E., Lee, G. R., Kim, S. T., Bartsevich, V. V., & Flavell, R. A. (2004) · Immunity · doi:10.1016/j.immuni.2004.10.015 · Cited by 189 · see citing works
Cutting Edge: Biasing Immune Responses by Directing Antigen to Macrophage Fcγ Receptors
Anderson, C. F., & Mosser, D. M. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.8.3697 · Cited by 178 · see citing works
Self-citationA Defect in Nucleosome Remodeling Prevents IL-12(p35) Gene Transcription in Neonatal Dendritic Cells
Goriely, S., Lint, C. M. V., Dadkhah, R., Libin, M., Wit, D. D., Demonté, D., Willems, F., & Goldman, M. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031272 · Cited by 165 · see citing works
GATA-3 Directly Remodels the IL-10 Locus Independently of IL-4 in CD4+ T Cells
Shoemaker, J., Saraiva, M., & O’Garra, A. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.6.3470 · Cited by 138 · see citing works
Zhou, L., Nazarian, A. A., & Smale, S. T. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.6.2385-2396.2004 · Cited by 113 · see citing works
Liu, Y., Chen, C.-C., Tseng, H.-P., & Chang, W. (2006) · Cellular Signalling · doi:10.1016/j.cellsig.2005.12.001 · Cited by 103 · see citing works
Chromatin-level Regulation of the IL10 Gene in T Cells
Im, S.-H., Hueber, A., Monticelli, S., Kang, K.-H., & Rao, A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401722200 · Cited by 103 · see citing works
IL-10 subfamily members: IL-19, IL-20, IL-22, IL-24 and IL-26
Conti, P., Kempuraj, D., Frydas, S., Kandere‐Grzybowska, K., Boucher, W. S., Létourneau, R., Madhappan, B., Sagimoto, K., Christodoulou, S., & Theoharides, T. C. (2003) · Immunology Letters · doi:10.1016/s0165-2478(03)00087-7 · Cited by 93 · see citing works
Structural Features of the Interleukin-10 Family of Cytokines
Zdanov, A. S. (2004) · Current Pharmaceutical Design · doi:10.2174/1381612043382602 · Cited by 69 · see citing works
Cross-talking histones: implications for the regulation of gene expression and DNA repair
Wood, A., Schneider, J., & Shilatifard, A. (2005) · Biochemistry and Cell Biology · doi:10.1139/o05-116 · Cited by 52 · see citing works
Waage, A., & Aasen, A. O. (1992) · Immunological Reviews · doi:10.1111/j.1600-065x.1992.tb01416.x · Cited by 52 · see citing works
Regulation of Ultraviolet B-induced Phosphorylation of Histone H3 at Serine 10 by Fyn Kinase
He, Z., Cho, Y., Ma, W., Choi, H. S., Bode, A. M., & Dong, Z. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402053200 · Cited by 49 · see citing works
Transcriptional Activation: Mediator Can Act after Preinitiation Complex Formation
Struhl, K. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.03.002 · Cited by 18 · see citing works
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Villagra, A., Cheng, F., Wang, H.-W., Suarez, I., Glozak, M., Maurin, M., Nguyen, D., Wright, K. L., Atadja, P. W., Bhalla, K., et al. (2009) · Nature Immunology · doi:10.1038/ni.1673 · Cited by 455 · see citing works
Genomic views of STAT function in CD4+ T helper cell differentiation
O'Shea, J. J., Lahesmaa, R., Vahedi, G., Laurence, A., & Kanno, Y. (2011) · Nature Reviews Immunology · doi:10.1038/nri2958 · Cited by 295 · see citing works
Mylonas, K. J., Nair, M. G., Prieto-Lafuente, L., Paape, D., & Allen, J. E. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803463 · Cited by 140 · see citing works
Cheng, F., Lienlaf, M., Perez-Villarroel, P., Wang, H.-W., Lee, C., Woan, K., Woods, D., Knox, T., Bergman, J., Pinilla-Ibarz, J., et al. (2014) · Molecular Immunology · doi:10.1016/j.molimm.2014.02.019 · Cited by 140 · see citing works
A new aspect of chronic pain as a lifestyle-related disease
Senba, E., & Kami, K. (2017) · Neurobiology of Pain · doi:10.1016/j.ynpai.2017.04.003 · Cited by 57 · see citing works
- Authors
- Zhang, X., Edwards, J. P., & Mosser, D. M.
- Affiliations
- University of Maryland, College Park (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-07
- Volume
- 177
- Issue
- 2
- Pages
- 1282-1288
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2643023
- OpenAlex
- W2103235243
- Cited by
- 122
- References
- 32
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 6 · 2018: 5 · 2017: 6 · 2016: 8 · 2015: 2 · 2014: 12 · 2013: 7 · 2012: 4
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI49383, R01AI049383)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- IL-10, macrophages, histone H3 phosphorylation, histone acetylation, histone deacetylase, ERK activation, transcription factor binding, cytokine gene regulation, chromatin modification, transcriptional regulation
- MeSH terms
- Acetylation, Animals, Bone Marrow Cells, Cells, Cultured, Chromatin, Gene Expression Regulation, Histones, Kinetics, Lysine, Macrophages, Mice, Inbred BALB C, Phosphorylation, Promoter Regions, Genetic, Serine, Time Factors, Sp1 Transcription Factor, Interleukin-10, Protein Transport, Extracellular Signal-Regulated MAP Kinases, Mice
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