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 profile the transcriptome of human monocyte THP1 cells challenged with cGAMP, LPS, or IFNB1 protein as a function of knockout (KO) or overexpression (OE) of IRFs or KO of IFNAR2. We define distinct gene expression groups, reflecting the transcription factors responsible for their induction including subgroups activated by more than one pathway or feed-forward regulation. We compare 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 induces NF-κB responses in monocyte and macrophage state cells, however, IFNs and ISGs are only co-induced in the macrophage state requiring IRF3. IRF1, IRF2, IRF5, and IRF8 are 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.