Published online before print March 17, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1104652

Received for publication November 10, 2004.
Revised January 26, 2005.
Accepted for publication February 14, 2005.

Article

2-Arachidonoyl-glycerol suppresses interferon- production in phorbol ester/ionomycin-activated mouse splenoctyes independent of CB1 or CB2

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

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

Abstract

2-Arachidonoyl-glycerol (2-AG), an endogenous ligand for cannabinoid receptor types 1 and 2 (CB1 and CB2), has previously been demonstrated to modulate immune functions including suppression of interleukin-2 expression and nuclear factor of activated T cells (NFAT) activity. The objective of the present studies was to investigate the effect of 2-AG on interferon- (IFN-) expression and associated upstream signaling events. Pretreatment of splenocytes with 2-AG markedly suppressed phorbol 12-myristate 13-acetate plus calcium ionophore (PMA/Io)-induced IFN- secretion. In addition, 2-AG suppressed IFN- steady-state mRNA expression in a concentration-dependent manner. To unequivocally determine the putative involvement of CB1 and CB2, splenocytes derived from CB1^-/-/CB2^-/- knockout mice were used. No difference in the magnitude of IFN- suppression by 2-AG in wild-type versus CB1/CB2 null mice was observed. Time-of-addition studies revealed that 2-AG treatment up to 12 h post-cellular activation resulted in suppression of IFN-, which was consistent with a time course conducted with cyclosporin A, an inhibitor of NFAT activity. Coincidentally, 2-AG perturbed the nuclear translocation of NFAT protein and blocked thapsigargin-induced elevation in intracellular calcium, suggesting that altered calcium regulation might partly explain the suppression of NFAT nuclear translocation and subsequent IFN- production. Indeed, Io partially attenuated the 2-AG-induced suppression of PMA/Io-stimulated IFN- production. Taken together, these data demonstrate that 2-AG suppresses IFN- expression in murine splenocytes in a CB-independent manner and that the mechanism partially involves suppression of intracellular calcium signaling and perturbation of NFAT nuclear translocation.

Key Words: cannabinoid • nuclear factor of activated T cells

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