Impaired NFAT and NFκB activation are involved in suppression of CD40 ligand expression by Δ9-tetrahydrocannabinol in human CD4+ T cells

• Published in: Toxicology and applied pharmacology 2013-11, Vol.273 (1), p.209-218
• Main Authors: Ngaotepprutaram, Thitirat, Kaplan, Barbara L.F., Kaminski, Norbert E.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; CD40L; Drug addictions; Intracellular calcium; Medical sciences; NFAT; NFκB; T cell-receptor signaling; Toxicology; Δ9-tetrahydrocannabinol (Δ9-THC)
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.08.023

We have previously reported that Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive cannabinoid in marijuana, suppresses CD40 ligand (CD40L) expression by activated mouse CD4+ T cells. CD40L is involved in pathogenesis of many autoimmune and inflammatory diseases. In the present study, we investigated the molecular mechanism of Δ9-THC-mediated suppression of CD40L expression using peripheral blood human T cells. Pretreatment with Δ9-THC attenuated CD40L expression in human CD4+ T cells activated by anti-CD3/CD28 at both the protein and mRNA level, as determined by flow cytometry and quantitative real-time PCR, respectively. Electrophoretic mobility shift assays revealed that Δ9-THC suppressed the DNA-binding activity of both NFAT and NFκB to their respective response elements within the CD40L promoter. An assessment of the effect of Δ9-THC on proximal T cell-receptor (TCR) signaling induced by anti-CD3/CD28 showed significant impairment in the rise of intracellular calcium, but no significant effect on the phosphorylation of ZAP70, PLCγ1/2, Akt, and GSK3β. Collectively, these findings identify perturbation of the calcium-NFAT and NFκB signaling cascade as a key mechanistic event by which Δ9-THC suppresses human T cell function. •Δ9-THC attenuated CD40L expression in activated human CD4+ T cells.•Δ9-THC suppressed DNA-binding activity of NFAT and NFκB.•Δ9-THC impaired elevation of intracellular Ca2+.•Δ9-THC did not affect phosphorylation of ZAP70, PLCγ1/2, Akt, and GSK3β.