Marijuana and the Cannabinoids

268 Tashkin and Roth
methylxanthine all blocked the capacity for THC to induce TGF-β consistent with
signaling via cannabinoid receptors. Selective CB 1 or CB 2 receptor antagonists were
then used to confirm that signaling was mediated via the CB 2 receptor. It is entirely
possible that upregulation of TGF-β by THC mediates many of its immunological
consequences on human cells, as it does on mouse cells, but experiments to test this
hypothesis have not yet been carried out.
5.4. Immunological Suppression of Alveolar Macrophages
in the Lungs of Habitual Marijuana Smokers
The finding that peripheral blood leukocytes collected from marijuana smokers
express higher than normal levels of CB 1 and CB 2 mRNA (65), and that THC mediates
distinct immunoregulatory effects when cultured with human leukocytes in vitro
(68,86), provide only indirect evidence that marijuana smoking is associated with
immunological consequences. The most compelling and direct evidence is provided
by studies with AM recovered directly from the lungs of habitual marijuana users
(Table 2; refs. 41 and 42). AM are the primary immune cells residing in the distal air
spaces of the lung, where they take up and retain large amounts of inhaled tar (39). As
previously described, AM recovered from the lungs of marijuana smokers were found
to be significantly impaired in their ability to secrete pro-inflammatory cytokines and
to phagocytose and kill S. aureus, whereas AM from tobacco smokers performed normally
in these studies (41). It is very likely that THC, which is present only in the tar
generated from marijuana smoke, accounts for these functional abnormalities.
THC can alter specific cytoskeletal components involved in phagocytosis (tubulin
and actin) and inhibit macrophage-mediated phagocytosis in vitro (87). In addition
to producing defects in phagocytosis, THC can also impair the production of nitric
oxide (NO), a reactive nitrogen intermediate that serves as an important effector molecule
in bacterial killing (88). Using murine macrophage cell lines, several investigators
have demonstrated that THC suppresses lipopolysaccharide-induced production
of NO and subsequent antibacterial or antitumor activity (89–91). This effect is mediated
by cannabinoid receptors, involves inhibition of both cAMP and the NF-κB/Rel
family of transcription factors, and blocks the induction of mRNA encoding for
inducible nitric oxide synthase (iNOS) (91).
Inhaled THC appears to mediate the same effects in the lungs of marijuana smokers.
The etiology for this antimicrobial deficit was first suggested by inhibitor studies
using N G -monomethyly-L-arginine monoacetate (NGMMA), an inhibitor of NOS (41).
The addition of NGMMA to cultures containing AM from nonsmokers and tobacco
smokers inhibited their antibacterial killing activity, but this compound had no effect
when added to cultures containing AM from marijuana smokers. S. aureus, and its
isolated cell wall constituent protein A, are known to induce NO when used to stimulate
murine cells in vivo and/or in vitro (92,93). The investigators hypothesized that S.
aureus induced iNOS when added to cultures with AM from nonsmokers or smokers
of tobacco only, resulting in potent antimicrobial activity, but not when added to cells
recovered from marijuana smokers. To test this hypothesis, they used semi-quantitative
RT-PCR to measure mRNA levels encoding for iNOS in resting AM and following
co-culture with S. aureus (42). Release of NO was also determined by the