Abstract
We previously showed that increased IFNγ production by natural killer (NK) cells correlates with increased susceptibility to infection with Listeria monocytogenes. Here, we report that L. monocyogenes suppresses macrophage responsiveness to IFNγ and describe a mechanism contributing to this suppression. Macrophages infected with L. monocytogenes produced a soluble factor that reduced IFNGR1 transcripts and cell surface expression of both IFNGR1 and IFNGR2 proteins on infected and bystander macrophages and on certain other immune cells. We identify this factor as IFNβ or a substance induced by type I IFN, since (1) only L. monocytogenes strains that induce IFNβ caused IFNGR downregulation, (2) IFNGR downregulation was not seen in macrophages lacking a functional type I IFN receptor (IFNAR1-deficient mice), (3) IFNGR-downregulation was partially dependent on STAT1 and was induced by treatment of cells with recombinant IFNβ or IFNαβ -inducing toll like receptor (TLR) agonists. Our findings demonstrate that IFNβ induced during intracellular bacterial infection feeds back through IFNAR to inhibit IFNGR expression and IFNγ-dependent gene expression. These findings offer a common mechanistic explanation for the ability of IFNβ to enhance host susceptibility to intracellular bacterial infection and to suppress inflammation in the context of diseases such as multiple sclerosis.
