T helper cell type 1 (Th1)-polarizing
cytokines are induced by
Legionella pneumophila infection and are suppressed by pretreatment with marijuana
cannabinoids (CB).
Glucocorticoids and
prostaglandin E2(
PGE2) are also reported to suppress Th1 polarization and are induced by Delta9-tetrahydrocannabinol (
THC), so their role in the suppression of polarizing
cytokines was examined. Injection of L. pneumophila or
THC alone into BALB/c mice induced a rapid and transient rise in serum
corticosterone (CS), and the injection of both agents significantly augmented the CS response, demonstrating that
THC increased CS in Legionella-infected mice. Pretreatment with the CB receptor 1 (CB1) antagonist
SR141716A had no effect on the
THC-induced CS response, but CB2 antagonist (
SR144528) treatment increased the CS response. To see if increased CS contributed to the down-regulation of Th1
cytokines, mice were pretreated with the
steroid antagonist
RU486 before
THC injection and Legionella
infection. The results showed that
RU486 did not attenuate the
THC-induced suppression of serum
interleukin (IL)-12 or
interferon-gamma (IFN-gamma). In addition to CS,
THC injection increased urinary
PGE2 metabolites, and the CB1 antagonist attenuated this increase. Although L. pneumophila
infection increased urinary
PGE2,
THC pretreatment did not enhance this response; in addition, treatment with the
cyclooxygenase inhibitor,
indomethacin, did not block the
THC-induced suppression of
IL-12 and IFN-gamma. These results suggest that the elevation of CS and
PGE2 does not account for the
THC-induced attenuation of the Th1
cytokine response, and it is concluded that other suppressive mediators are induced by
THC or that the drug acts directly on immune cells to suppress
cytokine production.