Differential modulation by delta9-tetrahydrocannabinol (∆9)-THC) of CD40 ligand (CD40L) expression in activated mouse splenic CD4+ T cells.

The anti-inflammatory activity of cannabinoids has been widely demonstrated in experimental animal models and in humans. CD40-CD40-ligand (L) interactions are among the most crucial initiators of inflammation. This study investigated the effects of ∆(9)-THC on CD40L expression in mouse splenic T cells after activation with various stimuli. Time course studies demonstrated that peak surface expression of CD40L by CD4(+) T cells after anti-CD3/CD28 or phorbol ester plus calcium ionophore (PMA/Io) occurred 8 h post activation. Peak CD40L mRNA levels were observed at 2 h post PMA/Io treatment and at 4 h post anti-CD3/CD28 treatment. Pretreatment with ∆(9)-THC significantly impaired the upregulation of CD40L induced by anti-CD3/CD28 at both the protein and mRNA level. By contrast, ∆(9)-THC did not affect PMA/Io-induced surface CD40L expression on CD4(+) T cells. Additionally, ∆(9)-THC also attenuated anti-CD3/CD28-induced CD40L expression on CD4(+) T cells derived from CB1(-/-)/CB2(-/-) mice. We investigated whether the mechanism by which ∆(9)-THC suppressed CD40L expression involved putative cannabinoid activation of the glucocorticoid receptor (GR). Although activation of GR resulted in suppression of CD40L induction by anti-CD3/CD28, no interaction between ∆(9)-THC and GR was observed by a glucocorticoid response element (GRE) luciferase reporter assay in HEK293T cells. Collectively, these results suggest that ∆(9)-THC targets proximal T cell receptor-associated signaling in a cannabinoid receptor- and glucocorticoid receptor-independent manner. These findings identify suppression of CD40L expression as a novel part of the mechanism by which ∆(9)-THC exerts anti-inflammatory activity.