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IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages.

Cell Rep. 2018 Oct 02;25(1):95-106.e6
Sinu P John 1 , Jing Sun 2 , Rebecca J Carlson 2 , Binh Cao 2 , Clinton J Bradfield 2 , Jian Song 3 , Margery Smelkinson 4 , Iain D C Fraser 5
Sinu P John 1 , Jing Sun 2 , Rebecca J Carlson 2 , Binh Cao 2 , Clinton J Bradfield 2 , Jian Song 3 , Margery Smelkinson 4 , Iain D C Fraser 5
+ et al

[No authors listed]

Author information
  • 1 Signaling Systems Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: sinu.john@nih.gov.
  • 2 Signaling Systems Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
  • 3 Bioinformatics Group, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
  • 4 Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
  • 5 Signaling Systems Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: fraseri@nih.gov.

摘要

Activation of the TLR4 signaling pathway by lipopolysaccharide (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.

KEYWORDS: IFIT1, RNAi screen, TLR4, TNF-α, interferon, interferon gene program, pro-inflammatory gene program

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