Ligand-induced IFNγ down regulation calibrates myeloid cell IFNγ responsiveness

Abstract

Abstract Inflammation triggers production of type II IFN (IFNγ), which induces expression of gamma-activated genes (GAGs) that enhance antigen presentation and antimicrobial activity associated with M1-type macrophage activation. Negative regulation of these responses is important to prevent excessive macrophage activity and inflammation. We report here that stimulation with IFNγ transiently reduces myeloid cell IFNGR to raise the threshold for STAT1 activation in response to subsequent IFNγ. IFNγ production contributed to reduced monocyte surface IFNGR during the first day after systemic Listeria monocytogenes (Lm) infection. IFNγ treatment also reduced IFNGR staining on cultured bone marrow derived macrophages (BMDM) and dendritic cells (BMDCs), and human monocytes. These reductions in IFNGR were independent of type I IFNs, the primary trigger for IFNGR reductions later after Lm infection. Reductions in IFNGR correlated with reduced macrophage ifngr1 transcript abundance but this was independent of effects on the proximal Ifngr1 promoter. IFNGR down regulation following a brief exposure to IFNγ was further observed to transiently reduce myeloid cell sensitivity to subsequent IFNγ, measured as induction of phosphorylated (p)STAT1. Prolonged or elevated IFNγ could overcome the suppression of pSTAT1 activation. These data suggest transient IFNγ production reduces IFNGR to calibrate M1-type myeloid cell activation.