Differential Modulation by Delta(9)-Tetrahydrocannabinol (a dagger(9)-THC) of CD40 Ligand (CD40L) Expression in Activated Mouse Splenic CD4(+) T cells

作者：Ngaotepprutaram Thitirat; Kaplan Barbara L F; Crawford Robert B; Kaminski Norbert E^*

来源：Journal of Neuroimmune Pharmacology, 2012, 7(4): 969-980.

DOI：10.1007/s11481-012-9390-z

• Delta(9)-THC
• CD40L
• Anti-CD3/CD28
• PMA/Io
• CB1
• CB2
• Inflammatory diseases

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 a dagger(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 a dagger(9)-THC significantly impaired the upregulation of CD40L induced by anti-CD3/CD28 at both the protein and mRNA level. By contrast, a dagger(9)-THC did not affect PMA/Io-induced surface CD40L expression on CD4(+) T cells. Additionally, a dagger(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 a dagger(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 a dagger(9)-THC and GR was observed by a glucocorticoid response element (GRE) luciferase reporter assay in HEK293T cells. Collectively, these results suggest that a dagger(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 a dagger(9)-THC exerts anti-inflammatory activity.

• 出版日期2012-12