IFNbeta responses induced by intracellular bacteria or cytosolic DNA in different human cells do not require ZBP1 (DLM-1/DAI).
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 IFNalpha/beta 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 IFNbeta, full-length hZBP1 and a prominent splice variant lacking the first Zalpha domain (hZBP1DeltaZalpha) in human cells. Overexpression of hZBP1 but not hZBP1DeltaZalpha slightly amplified poly(dA-dT)-stimulated IFNbeta reporter activation in HEK293 cells, but had no effect on IFNbeta and IL-8 production induced by bacteria or poly(dA-dT) in A549 cells. We found that mZBP1 siRNA impaired poly(dA-dT)-induced IFNbeta responses in mouse L929 fibroblasts at a later time point, while multiple hZBP1 siRNAs did not suppress IFNbeta or IL-8 expression induced by poly(dA-dT) or bacterial infection in human cells. In contrast, IRF3 siRNA strongly impaired the IFNbeta responses to poly(dA-dT) or bacterial infection. In conclusion, intracellular bacteria and cytosolic poly(dA-dT) activate IFNbeta responses in different human cells without requiring human ZBP1.
Lippmann
Juliane
J
Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Rothenburg
Stefan
S
Deigendesch
Nikolaus
N
Eitel
Julia
J
Meixenberger
Karolin
K
van Laak
Vincent
V
Slevogt
Hortense
H
N'guessan
Philippe Dje
PD
Hippenstiel
Stefan
S
Chakraborty
Trinad
T
Flieger
Antje
A
Suttorp
Norbert
N
Opitz
Bastian
B
D000818:Animals; D002460:Cell Line; D004269:DNA, Bacterial / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis; D016952:Legionella pneumophila / Q000276:immunology*; D051379:Mice; D016601:RNA-Binding Proteins
D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D016209:Interleukin-8; D016601:RNA-Binding Proteins; C485731:ZBP1 protein, human; D016899:Interferon-beta