Working in negative space: Type I interferon mediated immuno-modulation through transcriptional suppression in disease and homeostasis

Abstract

The type I interferon family of cytokines are rapidly produced following innate pattern recognition receptor engagement and establish a critical early state of host defense. Type I interferons act in antiviral immunity as transcriptional activators and the binding of any type I interferon to the common IFNAR receptor triggers the transcription of Interferon Stimulated Genes (ISGs). A defined set of ISGs have been described through exhaustive studies and the protein products of these ISGs function to increase cell intrinsic resistance to viral growth and to promote viral clearance. Simultaneously, interferons also drive a much less well studied program of transcriptional suppression, inhibiting the expression of an unknown number of genes, with poorly understood consequences for disease. The limited number of genes currently known to be transcriptionally suppressed by IFN are enriched for those with immune-mediating activities such as inflammatory cytokines (e.g., IL-1β), cytokine receptors (e.g., IFNγR) and chemokines. Interferon dependent transcriptional suppression of immune response genes is therefore thought to underlie the immune suppression associated with interferon production during many bacterial infections (e.g., mycobacterium tuberculosis and listeria monocytogenes) and may also explain the palliative effects of interferons in some autoimmune diseases. Despite the health relevance of IFN driven transcriptional suppression, no consensus molecular model exists to explain its selectivity or regulation. In this review we highlight the current literature detailing the known targets of IFN transcriptional suppression within the various disease models in which it has been observed. We also review the relevant molecular mechanisms which have been proposed to explain transcriptional suppression by interferons and discuss the remaining open questions in this field with an ambition to stimulate future work in this area.

Keywords: CXCL2; IFN; IFNAR; IFNβ; IL-17; IRF9; ISG; ISGF3; JAK; STAT; Th17; Tyk2; Type i interferon; bacteria; bechets’ disease; candida albicans; immune suppression; immunosuppression; influenza; listeria monocytogenes; multiple sclerosis; mycobacterium tuberculosis; salmonella typhimurium; streptococcus pneumoniae; transcription; virus.

Figure 1.

Model of positive and negative gene regulation by type I interferons. (a) type I interferon activation of interferon stimulated gene (ISG) transcription requires the IFNAR induced assembly of the hetero-trimeric ISGF3 transcription factor. ISGF3 recognizes the ISRE sequence motif proximal to the promoter of ISGs and drives increased RNApolII dependent gene transcription. (b) Interferon dependent transcriptional suppression may proceed in a gene direct manner through ISGF3 dependent or independent transcriptional regulators including DNA binding transcriptional repressors recognizing a target motif within suppressed promoters and/or histone modifying enzymes. Alternatively, the product(s) of one or more upregulated ISGs, such as immunosuppressive cytokines, may function to suppress subsequent gene transcription.

Figure 2.

Type I IFN suppresses expression of genes from a variety of biological processes. GO pathway analysis of publicly available RNA-Seq data (GEO: GSE61055) generated using IFNβ treated mouse BMDMs. List of IFN down-regulated genes generated by comparing untreated and IFNβ treated samples. Differentially expressed genes identified using GEO2R (adjusted p < 0.05, Fold change < −1). GO analysis was performed using the enrichGO function from the clusterProfiler R package with ontology set to biological processes. Genes listed in each category represent top 3 nonredundant downregulated genes in that category.