Regulation of Inflammatory NF-kB Target Gene Activation by Jak-STAT Signaling

Abstract

Abstract Macrophages are key innate immune cells that are important for host defense but their aberrant activation by IFN-γ has been implicated in the pathogenesis of chronic inflammatory diseases such as rheumatoid arthritis (RA). IFN-γ, signals through protein tyrosine kinases JAK1/2 to activate transcription factor STAT1 and drive the expression of interferon-stimulated genes (ISGs). IFN-γ primed macrophage induced rapid and enhanced expression of both canonical and non-canonical ISGs when challenged with toll-like receptor 4 (TLR4) ligand (LPS). However, IFN-γ alone was not able to elicit the expression of the noncanonical ISGs that are considered proinflammatory NF-kB target genes. Based on this observation, we hypothesized that any inflammatory stimuli can synergistically activate NF-kB target genes in IFN-γ primed macrophages. Like LPS, TLR2 ligand (PAM3) synergistically induced NF-kB target genes expression but inflammatory cytokine TNF-α failed to do so in IFN-γ primed macrophages. The primed macrophage is similar to RA macrophage where JAK signaling is ongoing and STAT1 is activated in tandem with inflammatory NF-kB signaling. Our model suggests that targeted inhibition of JAK1/2 could be a potential strategy to inhibit the production of inflammatory cytokines by these macrophages. To address this, we used an FDA-approved JAK1/2 inhibitor for RA. JAK inhibition effectively suppressed the expression of a subset of IFN-γ-induced genes, whereas LPS induced genes remained partially resistant to inhibition. This suggests that IFN-γ priming induces long term epigenetic memory which persist even after inhibition of IFN-γ signaling.