Dissection of innate-immune-ligand- and interferon-protein-mediated transcriptional responses in human THP1 cell states

Interferon regulatory factors (IRFs) are essential for transcription of interferons (IFNs), interferon-stimulated genes (ISGs), and pro-inflammatory cytokines. We profiled the transcriptome of human monocyte THP1 cells challenged with cGAMP, LPS, or IFNB1 protein as a function of knockout (KO) or overexpression (OE) of individual IRFs or a combination thereof. We defined distinct groups of gene expression based on the various treatments and their dependence on IRFs and IFNAR2. We compared IRF3- and IRF7-induced gene signatures and note the strong direct induction of a subset of antiviral-acting ISGs by IRF3 or IRF7. LPS treatment induced NF-kB responses in macrophage and monocyte state cells, however, IFNs and ISGs were only co-induced in the macrophage state requiring IRF3. IRF1, IRF2, IRF5, and IRF8 were largely dispensable for IFN-stimulated or innate-immune-mediated gene induction. This study provides a valuable resource for dissecting complex inflammatory gene signatures and their underlying transcription factors thereby anticipating the effects of selectively drugging the underlying pathways.