title: Suppression of T cell costimulator ICOS by Delta9-tetrahydrocannabinol.
abstract: Inducible costimulator (ICOS), a prototypic T cell costimulator, is induced on activated T cells. ICOS regulates T cell activation and Th cell differentiation and is principally involved in humoral immune responses. Previous work showed that T cell accessory function is modulated by the plant-derived cannabinoid, delta-9-tetrahydrocannabinol (Delta(9)-THC). In light of an emerging role by ICOS in T cell-mediated immunity, the objective of this study was to investigate the effect of Delta(9)-THC on ICOS in activated mouse T cells. Induction of ICOS mRNA levels by phorbol ester (PMA) plus ionomycin (Io) activation in mouse splenocytes was attenuated by Delta(9)-THC in a concentration-related manner. Similar results were obtained in the mouse T cell line, EL4.IL-2. Anti-CD3/CD28 induced ICOS expression on CD4(+) splenic T cells, which was suppressed by Delta(9)-THC in a time- and concentration-related manner. The PMA/Io-induced icos promoter luciferase reporter activity was also down-regulated by Delta(9)-THC, suggesting that the suppression of ICOS expression by Delta(9)-THC occurs at the transcriptional level. Moreover, transcriptional activation of the NFAT was also down-regulated by Delta(9)-THC as shown by a NFAT luciferase reporter assay, which is consistent with a putative role of NFAT in regulating ICOS expression. Collectively, Delta(9)-THC suppresses ICOS expression in activated T cells, and this suppression may be related, in part, to its modulation of NFAT signaling. The emerging role of ICOS in a wide range of immune-related diseases also suggests that it may represent a potential therapeutic target, which could be modulated by cannabinoid compounds.
authors.affiliation: Department of Pharmacology and Toxicology and Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA.
authors.forename: Haitian
authors.initials: H
authors.lastname: Lu
authors.forename: Barbara L F
authors.initials: BL
authors.lastname: Kaplan
authors.forename: Thitirat
authors.initials: T
authors.lastname: Ngaotepprutaram
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000941:Antigens / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics* / Q000378:metabolism*; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D013759:Dronabinol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D060889:Inducible T-Cell Co-Stimulator Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012756:Sheep; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000941:Antigens; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D017252:CD3 Complex; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D013759:Dronabinol