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IFN-β Increases Listeriolysin O-Induced Membrane Permeabilization and Death of Macrophages¹

Heather Zwaferink^*, Silvia Stockinger^*, Parastoo Hazemi, Rosa Lemmens-Gruber and Thomas Decker^2,*

^* Max F. Perutz Laboratories, Vienna Biocenter, Department of Microbiology and Immunobiology and Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria

Type I IFN (IFN-I) signaling is detrimental to cells and mice infected with Listeria monocytogenes. In this study, we investigate the impact of IFN-I on the activity of listeriolysin O (LLO), a pore-forming toxin and virulence protein released by L. monocytogenes. Treatment of macrophages with IFN-β increased the ability of sublytic LLO concentrations to cause transient permeability of the plasma membrane. At higher LLO concentrations, IFN-β enhanced the complete breakdown of membrane integrity and cell death. This activity of IFN-β required Stat1. Perturbation of the plasma membrane by LLO resulted in activation of the p38MAPK pathway. IFN-β pretreatment enhanced LLO-mediated signaling through this pathway, consistent with its ability to increase membrane damage. p38MAPK activation in response to LLO was independent of TLR4, a putative LLO receptor, and inhibition of p38MAPK neither enhanced nor prevented LLO-induced death. IFN-β caused cells to express increased amounts of caspase 1 and to produce a detectable caspase 1 cleavage product after LLO treatment. Contrasting recent reports with another pore-forming toxin, this pathway did not aid cell survival as caspase1-deficient cells were equally sensitive to lysis by LLO. Key lipogenesis enzymes were suppressed in IFN-β-treated cells, which may exacerbate the membrane damage caused by LLO.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Austrian Science Foundation (Fonds zur Förderung der wissenschaftlichen Forschung) through Grants AP17859 and P20522-B05 (to T.D.), SFB 28 (to T.D.), and a PhD fellowship (to H.Z.). Additional funding was provided by the Viennese Foundation for Research and Technology (HOPI Initiative; to T.D.).

² Address correspondence and reprint requests to Dr. Thomas Decker, Max-Perutz Laboratories, Vienna Biocenter, Department of Microbiology and Immunobiology, University of Vienna, Dr. Bohr-Gasse 9/4 1030 Vienna, Austria. E-mail address: thomas.decker{at}univie.ac.at

³ Abbreviations used in this paper: LLO, listeriolysin O; IFN-I, type I IFN; LDH, lactate dehydrogenase; 7AAD, 7-aminoactinomycin D; PS, phosphatidylserine.