Intracellular bacteria and cytosolic stimulation with DNA activate type I IFN responses independently of Toll-like receptors, most Nod-like receptors and RIG-like receptors. A recent study suggested that ZBP1 (DLM-1/DAI) represents the long anticipated pattern recognition receptor which mediates IFNα/β responses to cytosolic DNA in mice. Here we show that Legionella pneumophila infection, and intracellular challenge with poly(dA-dT), but not with poly(dG-dC), induced expression of IFNβ, full-length hZBP1 and a prominent splice variant lacking the first Zα domain (hZBP1ΔZα) in human cells. Overexpression of hZBP1 but not hZBP1ΔZα slightly amplified poly(dA-dT)-stimulated IFNβ reporter activation in HEK293 cells, but had no effect on IFNβ and IL-8 production induced by bacteria or poly(dA-dT) in A549 cells. We found that mZBP1 siRNA impaired poly(dA-dT)-induced IFNβ responses in mouse L929 fibroblasts at a later time point, while multiple hZBP1 siRNAs did not suppress IFNβ or IL-8 expression induced by poly(dA-dT) or bacterial infection in human cells. In contrast, IRF3 siRNA strongly impaired the IFNβ responses to poly(dA-dT) or bacterial infection. In conclusion, intracellular bacteria and cytosolic poly(dA-dT) activate IFNβ responses in different human cells without requiring human ZBP1.
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