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Published online before print July 16, 2004

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(Journal of Leukocyte Biology. 2004;76:854-861.)
© 2004 by Society for Leukocyte Biology

The THC-induced suppression of Th1 polarization in response to Legionella pneumophila infection is not mediated by increases in corticosterone and PGE₂

Catherine A. Newton^*, Tangying Lu^*, Stanley J. Nazian, Izabella Perkins^*, Herman Friedman^* and Thomas W. Klein^*,1

^* Departments of Medical Microbiology and Immunology and
Physiology and Biophysics, University of South Florida, College of Medicine, Tampa

¹Correspondence: University of South Florida, College of Medicine, MDC Box 10, 12901 Bruce Downs Blvd., Tampa, FL 33612. E-mail: tklein{at}hsc.usf.edu

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 ⁹-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- (IFN-). 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-. 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.

Key Words: cannabinoids • Th2 cells • IL-12 • prostaglandins

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