CB1 and CB2 Cannabinoid Receptors Mediate Different Aspects of Delta-9-Tetrahydrocannabinol (THC)-Induced T Helper Cell Shift Following Immune Activation by Legionella Pneumophila Infection

Legionella pneumophila infection of mice induces proinflammatory cytokines and Th1 immunity as well as rapid increases in serum levels of IL-12 and IFN gamma and splenic IL-12R beta 2 expression. Delta-9-tetrahydrocannabinol (THC) treatment prior to infection causes a shift from Th1 to Th2 immunity and here we demonstrate that CB1 and CB2 cannabinoid receptors mediate different aspects of the shift. Using cannabinoid receptor antagonists and cannabinoid receptor gene deficient mice (CB1 (-/-) and CB2 (-/-)), we showed that both CB1 and CB2 receptors were involved in the THC-induced attenuation of serum IL-12 and IFN gamma. IFN gamma production is dependent upon signaling through IL-12R beta 2 (beta 2) and THC treatment suppressed splenic beta 2 message; moreover, this effect was CB1 but not CB2-dependent from studies with receptor antagonists and CB1(-/-) and CB2(-/-) mice. Furthermore, observed increases in IL-4 induced by THC, were not involved in the drug effect on beta 2 from studies with IL-4 deficient mice. The GATA-3 transcription factor is necessary for IL-4 production and is selectively expressed in Th2 cells. GATA-3 message levels were elevated in spleens of THC-treated and L. pneumophila-infected mice and the effect was shown to be CB2 but not CB1-dependent. Furthermore, GATA-3 regulatory factors were modulated in that Notch ligand Delta4 mRNA was decreased and Jagged1 increased by THC also in a CB2-dependent manner and splenic NF kappa B p65 was increased. Together, these results indicate that CB1 and CB2 mediate the THC-induced shift in T helper activity in L. pneumophila-infected mice, with CB1 involved in suppressing IL-12R beta 2 and CB2 involved in enhancing GATA-3.