title: Plasminogen activator inhibitor type 2 prevents programmed cell death of human macrophages infected with Mycobacterium avium, serovar 4.
abstract: Although Mycobacterium avium is usually nonpathogenic in healthy individuals, in vitro infection of macrophages (M phi) from the majority of healthy donors induces death of the cells 2 wk after infection; this effect is in contrast to noninfected M phi, which survive for months in culture. We demonstrate here that treatment of normal M phi with indomethacin further shortens the life of these cells to 48 h after infection with M. avium. Indomethacin treatment of the M phi also prevents M. avium-dependent accumulation of mRNA-encoding plasminogen activator inhibitor type-2 (PAI-2), an inhibitor of urokinase-type plasminogen activator. Occurrence of nuclear condensation and DNA fragmentation in M phi pretreated with indomethacin and infected with M. avium indicates that the early death of these cells is caused by apoptosis. In contrast, priming of M phi with GM-CSF significantly prolongs their survival after M. avium infection and enhances M. avium-induced accumulation of PAI-2 mRNA. Most importantly, addition of PAI-2 is sufficient to prevent apoptosis of M phi infected with M. avium in the presence of indomethacin. Finally, M phi not treated with indomethacin also die of apoptosis 7 to 10 days after M. avium infection and can be rescued by PAI-2. These studies indicate that production of PAI-2 by normal M phi as a consequence of M. avium infection inhibits programmed cell death, a mechanism that might serve to prevent the spread of the infection.
authors.affiliation: Department of Rheumatology/Immunology, Brigham and Womens' Hospital, Boston, MA 02115, USA.
authors.forename: H
authors.initials: H
authors.lastname: Gan
authors.forename: G W
authors.initials: GW
authors.lastname: Newman
authors.forename: H G
authors.initials: HG
authors.lastname: Remold
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000494:pharmacology; D002478:Cells, Cultured; D004249:DNA Damage; D015232:Dinoprostone / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000382:microbiology; D009162:Mycobacterium avium / Q000502:physiology*; D010894:Piroxicam / Q000494:pharmacology; D017396:Plasminogen Activator Inhibitor 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D013997:Time Factors
chemical_list: D017396:Plasminogen Activator Inhibitor 2; D012333:RNA, Messenger; D010894:Piroxicam; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015232:Dinoprostone; D001241:Aspirin; D007213:Indomethacin