Nitric Oxide is a Key Determinant of Group B Streptococcus-Induced Murine Macrophage Apoptosis
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Group B streptococcus (GBS; Streptococcus agalactiae) induces apoptosis of macrophages, and this may be an important mechanism GBS uses to suppress immune responses. The mechanisms whereby GBS induces apoptosis have not been identified. We studied GBS infection in murine macrophage-like J774A.1 cells and analyzed gene expression before apoptosis. Tumor necrosis factor (TNF)-a, interleukin (IL)-1, and inducible nitric oxide synthase (iNOS) gene expression coincided with apoptosis. Inhibition of iNOS gene expression by use of NG-monomethyl-L-arginine (NMMA) inhibited apoptosis, whereas inhibition of TNF-a and IL-1 biological activity did not. Macrophages from congenic iNOS-deficient mice were less susceptible to apoptosis than were macrophages from C57BL/6 mice. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) induced apoptosis without infection, confirming its proapoptotic effect. NMMA did not impair the microbicidal activity of macrophages, however, and SNAP was not bactericidal against GBS in vitro. In human monocyte-derived macrophages (HMDMs), NO production was minimal, even after costimulation with IFN-g and lipopolysaccharide. Dose-dependent apoptosis of HMDMs occurred without a significant NO response. Thus, NO is an important mediator of GBS-induced murine macrophage apoptosis but does not contribute to antimicrobial activity or cytotoxicity in HMDMs. HMDMs and murine macrophages are killed by GBS by alternative, NOindependent mechanisms. Future studies of host-cell machinery commandeered by GBS to bring about apoptosis will be important for understanding the role played by apoptosis in defense against this important human pathogen.
Journal of Infectious Diseases
Copyright 2005 by University of Chicago Press. First published in Journal of Infectious Diseases with publishing partner University of Chicago. Use hypertext link to access the journal's webpage. The attached file is reproduced here in accordance with the copyright policy of the publisher."