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

Abstract

Legionella pneumophila infection of mice induces proinflammatory cytokines and Th1 immunity as well as rapid increases in serum levels of IL-12 and IFNγ and splenic IL-12Rβ2 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 IFNγ. IFNγ production is dependent upon signaling through IL-12Rβ2 (β2) and THC treatment suppressed splenic β2 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 β2 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 NFκB 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-12Rβ2 and CB2 involved in enhancing GATA-3.

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Acknowledgements

We would like to thank Dr. Andreas Zimmer (University of Bonn, Germany) and Dr. Nancy Buckley (California State Polytechnic University) for CB deficient mice. This research was supported by NIH grants DA03646, AI45169, DA10683, and DA019824.

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Correspondence to Catherine A. Newton.

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Newton, C.A., Chou, PJ., Perkins, I. et al. 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. J Neuroimmune Pharmacol 4, 92–102 (2009). https://doi.org/10.1007/s11481-008-9126-2

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Keywords

  • THC
  • legionella
  • cannabinoid receptor
  • IL-12Rβ2
  • GATA-3