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IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages
Activation of the TLR4 signaling pathway by lipopoly-saccharide (LPS) leads to induction of both inflammatory and interferon-stimulated genes, but the mechanisms through which these coordinately activated transcriptional programs are balanced to promote an optimal innate immune response remain poorl...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492923/ https://www.ncbi.nlm.nih.gov/pubmed/30282041 http://dx.doi.org/10.1016/j.celrep.2018.09.002 |
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author | John, Sinu P. Sun, Jing Carlson, Rebecca J. Cao, Binh Bradfield, Clinton J. Song, Jian Smelkinson, Margery Fraser, Iain D.C. |
author_facet | John, Sinu P. Sun, Jing Carlson, Rebecca J. Cao, Binh Bradfield, Clinton J. Song, Jian Smelkinson, Margery Fraser, Iain D.C. |
author_sort | John, Sinu P. |
collection | PubMed |
description | Activation of the TLR4 signaling pathway by lipopoly-saccharide (LPS) leads to induction of both inflammatory and interferon-stimulated genes, but the mechanisms through which these coordinately activated transcriptional programs are balanced to promote an optimal innate immune response remain poorly understood. In a genome-wide small interfering RNA (siRNA) screen of the LPS-induced tumor necrosis factor α (TNF-α) response in macrophages, we identify the interferon-stimulated protein IFIT1 as a negative regulator of the inflammatory gene program. Transcriptional profiling further identifies a positive regulatory role for IFIT1 in type I interferon expression, implicating IFIT1 as a reciprocal modulator of LPS-induced gene classes. We demonstrate that these effects of IFIT1 are mediated through modulation of a Sin3A-HDAC2 transcriptional regulatory complex at LPS-induced gene loci. Beyond the well-studied role of cytosolic IFIT1 in restricting viral replication, our data demonstrate a function for nuclear IFIT1 in differential transcriptional regulation of separate branches of the LPS-induced gene program. |
format | Online Article Text |
id | pubmed-6492923 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
spelling | pubmed-64929232019-05-01 IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages John, Sinu P. Sun, Jing Carlson, Rebecca J. Cao, Binh Bradfield, Clinton J. Song, Jian Smelkinson, Margery Fraser, Iain D.C. Cell Rep Article Activation of the TLR4 signaling pathway by lipopoly-saccharide (LPS) leads to induction of both inflammatory and interferon-stimulated genes, but the mechanisms through which these coordinately activated transcriptional programs are balanced to promote an optimal innate immune response remain poorly understood. In a genome-wide small interfering RNA (siRNA) screen of the LPS-induced tumor necrosis factor α (TNF-α) response in macrophages, we identify the interferon-stimulated protein IFIT1 as a negative regulator of the inflammatory gene program. Transcriptional profiling further identifies a positive regulatory role for IFIT1 in type I interferon expression, implicating IFIT1 as a reciprocal modulator of LPS-induced gene classes. We demonstrate that these effects of IFIT1 are mediated through modulation of a Sin3A-HDAC2 transcriptional regulatory complex at LPS-induced gene loci. Beyond the well-studied role of cytosolic IFIT1 in restricting viral replication, our data demonstrate a function for nuclear IFIT1 in differential transcriptional regulation of separate branches of the LPS-induced gene program. 2018-10-02 /pmc/articles/PMC6492923/ /pubmed/30282041 http://dx.doi.org/10.1016/j.celrep.2018.09.002 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article John, Sinu P. Sun, Jing Carlson, Rebecca J. Cao, Binh Bradfield, Clinton J. Song, Jian Smelkinson, Margery Fraser, Iain D.C. IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages |
title | IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages |
title_full | IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages |
title_fullStr | IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages |
title_full_unstemmed | IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages |
title_short | IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages |
title_sort | ifit1 exerts opposing regulatory effects on the inflammatory and interferon gene programs in lps-activated human macrophages |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492923/ https://www.ncbi.nlm.nih.gov/pubmed/30282041 http://dx.doi.org/10.1016/j.celrep.2018.09.002 |
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