Impaired NFAT and NF魏B activation are involved in suppression of CD40 ligand expression by 螖⁹-tetrahydrocannabinol in human CD4⁺ T cells

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• 作者：Thitirat Ngaotepprutaram ; Barbara L.F. Kaplan ; Norbert E. Kaminski
• 关键词：螖9-tetrahydrocannabinol (螖9-THC) ; T cell-receptor signaling ; Intracellular calcium ; NFAT ; NF魏B ; CD40L
• 刊名：Toxicology and Applied Pharmacology
• 出版年：15 November, 2013
• 年：2013
• 卷：273
• 期：1
• 页码：209-218
• 全文大小：1371 K

文摘

We have previously reported that 螖⁹-tetrahydrocannabinol (螖⁹-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 螖⁹-THC-mediated suppression of CD40L expression using peripheral blood human T cells. Pretreatment with 螖⁹-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 螖⁹-THC suppressed the DNA-binding activity of both NFAT and NF魏B to their respective response elements within the CD40L promoter. An assessment of the effect of 螖⁹-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, PLC纬1/2, Akt, and GSK3尾. Collectively, these findings identify perturbation of the calcium-NFAT and NF魏B signaling cascade as a key mechanistic event by which 螖⁹-THC suppresses human T cell function.