Drugs of Abuse, Immunomodulation, and Aids

Newton, C, Klein, T, Friedman, H, Newton, Catherine, Klein, Thomas, Friedman, Herman, Catherine Newton, Thomas Klein, Herman Friedman

Delta-9-tetrahydrocannabinol (THC) has been shown to decrease Th1 responses (cell mediated immunity) while increasing Th2 responses (humoral immunity), both in vitro and in vivo. The addition of THC to murine splenocytes stimulated for 72 hrs with pokeweed mitogen (PWM) increased the detection of IL-4 and IL-10, cytokines associated with Th2 responses, and decreased IFN-gamma, IL-15 and IL-12, cytokines associated with Th1 responses. To investigate the cellular molecular basis for these effects of THC, cell depletion studies were performed. Removal of macrophages from the cell cultures eliminated the increase in IL-4 activity. This effect was observed when the macrophages were depleted during the first few hours but not after 24 hrs. Thus, it appears that the macrophages were producing an early factor responsible for the IL-4 increase. To examine the direct effect of THC on macrophages, peritoneal macrophages were cultured with various stimulators in the presence of THC. It was found that THC suppressed IL-12, IL-15 and IL-6 and increased IL-1 alpha, IL-1 beta, and TNF alpha in all of the stimulated cultures. IL-12 and IL-15 are known to induce IFN gamma production from T cells and NK cells and to be involved in the induction a Th1 response, while IL-1 is considered a growth factor for Th2 cells. Thus, the effects of THC on macrophages reflects the basic observation that THC decreases Th1 responses and increases Th2 responses. The data obtained adds to the understanding of the THC-induced Th1/Th2 shift, but the mechanisms still must be determined. However, the results of these studies do suggest that, in addition to lymphocytes, THC affects macrophages in splenocyte cultures and that the macrophages are involved in the alternation of the cytokines. Furthermore, the data demonstrate the diversity of the immunomodulatory effects THC exerts.