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Inhibition of MAPK and NF-B Pathways Is Necessary for Rapid Apoptosis in Macrophages Infected with Yersinia¹

Yue Zhang^*, Adrian T. Ting, Kenneth B. Marcu^, and James B. Bliska^2,*

Departments of^* Molecular Genetics and Microbiology, and Center for Infectious Diseases, and Biochemistry and Cell Biology, Institute for Cell and Developmental Biology, State University of New York, Stony Brook, NY 11794; Immunobiology Center, Mount Sinai School of Medicine, New York, NY 10029; and CRBA Laboratory, St. Orsola University Hospital, University of Bologna, Bologna, Italy

Macrophages respond to infection with pathogenic Yersinia species by activating MAPK- and NF-B-signaling pathways. To counteract this response, Yersiniae secrete a protease (Yersinia outer protein J (YopJ)) that is delivered into macrophages, deactivates MAPK- and NF-B-signaling pathways, and induces apoptosis. NF-B promotes cell survival by up-regulating expression of several apoptosis inhibitor genes. Previous studies show that deactivation of the NF-B pathway by YopJ is important for Yersinia-induced apoptosis. To determine whether deactivation of the NF-B pathway is sufficient for Yersinia-induced apoptosis, two inhibitors of the NF-B pathway, IB superrepressor or A20, were expressed in macrophages. Macrophages expressing these proteins were infected with Yersinia pseudotuberculosis strains that secrete functionally active or inactive forms of YopJ. Apoptosis levels were substantially higher (5- to 10-fold) when active YopJ was delivered into macrophages expressing IB superrepressor or A20, suggesting that deactivation of the NF-B pathway is not sufficient for rapid Yersinia-induced apoptosis. When macrophages expressing A20 were treated with specific inhibitors of MAPKs, similar levels of apoptosis (within 2-fold) were observed when active or inactive YopJ were delivered during infection. These results suggest that MAPK and NF-B pathways function together to up-regulate apoptosis inhibitor gene expression in macrophages in response to Yersinia infection and that YopJ deactivates both pathways to promote rapid apoptosis. In addition, treating macrophages with a proteasome inhibitor results in higher levels of infection-induced apoptosis than can be achieved by blocking NF-B function alone, suggesting that proapoptotic proteins are stabilized when proteasome function is blocked in macrophages.

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