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Published online before print November 6, 2008
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0608390

Received for publication June 30, 2008.
Revised October 14, 2008.
Accepted for publication October 18, 2008.

Article

Suppression of T cell costimulator ICOS by {Delta}9-tetrahydrocannabinol

Haitian Lu , Barbara L. F. Kaplan , Thitirat Ngaotepprutaram , and Norbert E. Kaminski @

Department of Pharmacology and Toxicology and Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA

@ To whom correspondence should be addressed. E-mail: kamins11{at}msu.edu.


  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.

Key Words: cannabinoid • splenocyte • NFAT • immunomodulation






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