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Vol. 286, Issue 2, 1103-1109, August 1998
9-Tetrahydrocannabinol Induces Apoptosis in
Macrophages and Lymphocytes: Involvement of Bcl-2 and
Caspase-11
Department of Medical Microbiology and Immunology, University of
South Florida, College of Medicine, Tampa, Florida
Apoptosis is programed cell death characterized by certain cellular
changes and regulated by various gene products including Bcl-2 and
caspase-1. The marijuana cannabinoid,
9tetrahydrocannabinol (THC), has been reported to
suppress in culture the proliferation of splenocytes and increase the
release of IL-1 from macrophages; however, the mechanisms of these
effects remain unclear. Because cannabinoids have also been reported to
induce apoptosis and because the release of IL-1 and suppression of
lymphoproliferation are related to apoptosis, we tested for the
induction of apoptosis by THC in murine immune cell cultures.
Splenocytes cultured with Con A for up to 24 hr showed evidence of DNA
fragmentation determined by gel electrophoresis, terminal
deoxynucleotide transferase-mediated dUTP-fluorescein nick end labeling
and 3H-thymidine labeling and THC (15-30 µM) treatment
increased fragmentation under these conditions. Resident peritoneal
macrophages cultured with lipopolysaccharides showed no obvious
fragmentation unless they were also treated with THC. Time course
studies examining DNA fragmentation and cell membrane integrity
(assessed by dye exclusion) showed that fragmentation preceded membrane
damage indicating that THC induced apoptosis rather than cell necrosis. In addition, THC treatment of splenocytes resulted in a decrease of
Bcl-2 mRNA and protein as measured by Northern and Western blotting,
respectively, and the drug induced apoptosis was blocked by the caspase
inhibitor, Ac-Tyr-Val-Ala-L-aspartic acid aldehyde. These
data suggest that THC treatment of cultured immune cells induces
apoptosis through the regulation of Bcl-2 and caspase activity.
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