Plasminogen activator inhibitor type 2 prevents programmed cell death of human macrophages infected with Mycobacterium avium, serovar 4.
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.
Gan
H
H
Department of Rheumatology/Immunology, Brigham and Womens' Hospital, Boston, MA 02115, USA.
Newman
G W
GW
Remold
H G
HG
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
D017396:Plasminogen Activator Inhibitor 2; D012333:RNA, Messenger; D010894:Piroxicam; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015232:Dinoprostone; D001241:Aspirin; D007213:Indomethacin