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Transcriptional control of the inflammatory response

Nature Reviews Immunology volume 9, pages 692–703 (2009)Cite this article

Key Points

  • A key point of control of inflammation is at the level of transcription.

  • In macrophages, which are key orchestrators of the inflammatory response, transcriptional control of inflammation enables the autonomous modulation of different functional programmes, such as cell migration, antimicrobial defence, tissue repair and phagocytosis.

  • Three classes of transcription factors (constitutively expressed, inducible in a stimulus-dependent manner and lineage-specifying) have distinct but coordinated functions in regulating the inflammatory response in macrophages.

  • The transcriptional response induced by Toll-like receptor signalling in macrophages is a well-studied model system for understanding transcriptional control of inflammation. This complex gene expression programme can be divided into a primary and secondary response, which are regulated by distinct mechanisms.

  • Many physiological signals negatively regulate inflammation at the transcriptional level. This also enables the inhibition of distinct functional modules of the inflammatory response.

Abstract

Inflammation is a multicomponent response to tissue stress, injury and infection, and a crucial point of its control is at the level of gene transcription. The inducible inflammatory gene expression programme — such as that triggered by Toll-like receptor signalling in macrophages — is comprised of several coordinately regulated sets of genes that encode key functional programmes; these are controlled by three classes of transcription factors, as well as various transcriptional co-regulators and chromatin modifications. Here, we discuss the mechanisms of and the emerging principles in the transcriptional regulation of inflammatory responses in diverse physiological settings.

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Figure 1: Lipopolysaccharide (LPS)-induced primary and secondary response genes are regulated by three categories of transcription factors.
Figure 2: Two distinct modes for regulating inducible genes.
Figure 3: Control of inflammatory gene expression by co-activators and co-repressors.

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Acknowledgements

We would like to thank D. Hargreaves, S. Foster and S. Smale for discussions. R.M. is an Investigator at the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Ruslan Medzhitov

  2. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Tiffany Horng

  3. Tiffany Horng

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Glossary

Adipose tissue

A type of connective tissue that is specialized for the storage of neutral lipids.

Transcription factor

A specialized nuclear protein that can bind to DNA and regulate gene expression. Most transcription factors have transactivation or repressor domains but, in addition, they can function as architectural proteins and promote chromatin remodelling by recruiting additional activator or repressor complexes.

Chromatin

Chromation is composed of DNA together with histones and other associated proteins.

Transcriptional co-regulator

Transcriptional co-regulators lack DNA-binding specificity and must be recruited to their target genes through interactions with transcription factors or by binding to particular chromatin modifications. Co-regulators have an important role in modulating gene expression and in many cases couple transcription factors to downstream effector mechanisms for gene regulation.

Small interfering RNA (siRNA)-mediated knockdown

Double-stranded RNAs (dsRNAs) with sequences that precisely match a given gene can 'knockdown' the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript. The two most common forms of dsRNA used for gene silencing are short — usually 21-base pair long — siRNAs or the plasmid-delivered short hairpin RNAs (shRNAs).

Polycomb proteins

A group of proteins that are required to maintain the silencing of genes encoding key developmental regulators, such as Hox.

Nucleosome

This is the basic repeating unit of eukaryotic genomes. Nucleosomes consist of 146 base pairs of DNA wound around an octamer of histone proteins.

SWI–SNF

(switching-defective–sucrose non-fermenting). An ATP-dependent chromatin remodelling protein complex that was first identified in yeast. Related complexes exist in mammals (where they are known as BAF) and are involved in the chromatin remodelling of various genes.

CpG island

A sequence of 0.5–2 kilobases that is rich in CpG dinucleotides. They are mostly located upstream of housekeeping genes and also of some tissue-specific genes, and they coincide with gene promoters in these contexts. In mammalian cells, most CpG islands are hypomethylated with respect to the rest of the genome.

Transcriptional co-repressor

Transcriptional co-repressors are protein complexes, including NCOR and SMRT, that associate with nuclear hormone receptors and other transcriptional regulators to inhibit gene transcription. A common mechanism of repression is by recruiting histone-deacetylase complexes to reverse the actions of histone acetyltransferases.

CBP–p300

CREB-binding protein (CBP) and p300 are transcriptional co-activators that interact with many transcription factors to promote recruitment of the RNA polymerase holoenzyme and other transcriptional regulators, thereby allowing transcriptional induction. In addition, p300 and CBP have histone acetyltransferase activity, such that these proteins can influence chromatin activity by modulating nucleosomal histones.

Histone acetyltransferase

A protein that acetylates core histones on lysine residues, which has important regulatory effects on chromatin structure and assembly, and on gene transcription. In general, increased levels of histone acetylation are associated with activation of gene expression.

Histone deacetylase

A protein that removes the acetyl groups from lysine residues that are located at the amino termini of histones. In general, decreased levels of histone acetylation are associated with the repression of gene expression. The balance of histone acetylation is maintained by the interplay between histone deacetylases and histone acetyltransferases.

Endotoxic shock

A clinical condition that is induced by hyper-reaction of the innate immune system to bacterial LPS. It is mediated by the inflammatory cytokines IL-1 and TNF, which are produced in large amounts due to sustained stimulation of TLR4 by LPS.

Septic shock

A systemic response to severe bacterial infections, which is generally caused by Gram-negative bacterial endotoxins, that leads to a hyperactive and out-of-balance network of inflammatory cytokines, affecting vascular permeability, cardiac function and metabolic balance. This can lead to tissue necrosis, multiple-organ failure and death.

Deacetylation

Acetylation is a post-translational modification of chromatin components, particularly histones, and other proteins. Histone deacetylases have been identified as components of nuclear co-repressor complexes.

Notch pathway

A pathway comprising highly conserved transmembrane receptors that regulate cell-fate choice in the development of many cell lineages, and so are crucial for the regulation of embryonic differentiation and development.

MicroRNAs

Single-stranded RNA molecules of approximately 21–23 nucleotides in length that are thought to regulate the expression of other genes.

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Medzhitov, R., Horng, T. Transcriptional control of the inflammatory response. Nat Rev Immunol 9, 692–703 (2009). https://doi.org/10.1038/nri2634

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