Abstract：
:AM404 is a synthetic TRPV1/CB(1) hybrid ligand with inhibitory activity on the anandamide transporter and is used for the pharmacological manipulation of the endocannabinoid system. It has been recently described that acetaminophen is metabolised in the brain to form the bioactive N-acylphenolamine AM404 and therefore, we have evaluated the effect of this metabolite in human T cells, discovering that AM404 is a potent inhibitor of TCR-mediated T-cell activation. Moreover, we found that AM404 specifically inhibited both IL-2 and TNF-alpha gene transcription and TNF-alpha synthesis in CD3/CD28-stimulated Jurkat T cells in a FAAH independent way. To further characterize the biochemical inhibitory mechanisms of AM404, we examined the signaling pathways that regulate the activation of the transcription factors NF-kappaB, NFAT and AP-1 in Jurkat cells. We found that AM404 inhibited both the binding to DNA and the transcriptional activity of endogenous NFAT and the transcriptional activity driven by the over expressed fusion protein Gal4-NFAT (1-415). However, AM404 did not affect early steps in NFAT signaling such as CD3-induced calcium mobilization and NFAT1 dephosphorylation. The NFAT inhibitory activity of AM404 seems to be quite specific since this compound did not interfere with the signaling pathways leading to AP-1 or NF-kappaB activation. These findings provide new mechanistic insights into the immunological effects of AM404 which in part could explain some of the activities ascribed to the widely used acetaminophen.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Caballero FJ,Navarrete CM,Hess S,Fiebich BL,Appendino G,Macho A,Muñoz E,Sancho Rdoi
10.1016/j.bcp.2006.12.001subject
Has Abstractpub_date
2007-04-01 00:00:00pages
1013-23issue
7eissn
0006-2952issn
1873-2968pii
S0006-2952(06)00807-0journal_volume
73pub_type
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pub_type： 杂志文章
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pub_type： 杂志文章,评审
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pub_type： 杂志文章
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pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：1996-11-08 00:00:00
