IFN-beta increases listeriolysin O-induced membrane permeabilization and death of macrophages.
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-beta increased the ability of sublytic LLO concentrations to cause transient permeability of the plasma membrane. At higher LLO concentrations, IFN-beta enhanced the complete breakdown of membrane integrity and cell death. This activity of IFN-beta required Stat1. Perturbation of the plasma membrane by LLO resulted in activation of the p38MAPK pathway. IFN-beta 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-beta 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 caspase 1-deficient cells were equally sensitive to lysis by LLO. Key lipogenesis enzymes were suppressed in IFN-beta-treated cells, which may exacerbate the membrane damage caused by LLO.
Zwaferink
Heather
H
Max F. Perutz Laboratories, Vienna Biocenter, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.
Stockinger
Silvia
S
Hazemi
Parastoo
P
Lemmens-Gruber
Rosa
R
Decker
Thomas
T
D000276:Adjuvants, Immunologic / Q000502:physiology / Q000633:toxicity; D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity; D016923:Cell Death / Q000276:immunology; D002463:Cell Membrane Permeability / Q000276:immunology*; D002478:Cells, Cultured; D003603:Cytotoxins / Q000502:physiology; D006360:Heat-Shock Proteins / Q000502:physiology* / Q000633:toxicity; D006460:Hemolysin Proteins / Q000502:physiology* / Q000633:toxicity; D016899:Interferon-beta / Q000502:physiology* / Q000633:toxicity; D007739:L Cells; D008089:Listeria monocytogenes / Q000254:growth & development / Q000276:immunology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*
D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D003603:Cytotoxins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D016899:Interferon-beta; C038705:hlyA protein, Listeria monocytogenes