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2-Arachidonoyl-glycerol suppresses interferon-gamma production in phorbol ester/ionomycin-activated mouse splenocytes independent of CB1 or CB2.
J Leukoc Biol 2005; 77(6):966-74JL

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-gamma (IFN-gamma) 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-gamma secretion. In addition, 2-AG suppressed IFN-gamma 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-gamma 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-gamma, 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-gamma production. Indeed, Io partially attenuated the 2-AG-induced suppression of PMA/Io-stimulated IFN-gamma production. Taken together, these data demonstrate that 2-AG suppresses IFN-gamma expression in murine splenocytes in a CB receptor-independent manner and that the mechanism partially involves suppression of intracellular calcium signaling and perturbation of NFAT nuclear translocation.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, 48824, USA. kamins11@msu.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15774549

Citation

Kaplan, Barbara L F., et al. "2-Arachidonoyl-glycerol Suppresses Interferon-gamma Production in Phorbol Ester/ionomycin-activated Mouse Splenocytes Independent of CB1 or CB2." Journal of Leukocyte Biology, vol. 77, no. 6, 2005, pp. 966-74.
Kaplan BL, Ouyang Y, Rockwell CE, et al. 2-Arachidonoyl-glycerol suppresses interferon-gamma production in phorbol ester/ionomycin-activated mouse splenocytes independent of CB1 or CB2. J Leukoc Biol. 2005;77(6):966-74.
Kaplan, B. L., Ouyang, Y., Rockwell, C. E., Rao, G. K., & Kaminski, N. E. (2005). 2-Arachidonoyl-glycerol suppresses interferon-gamma production in phorbol ester/ionomycin-activated mouse splenocytes independent of CB1 or CB2. Journal of Leukocyte Biology, 77(6), pp. 966-74.
Kaplan BL, et al. 2-Arachidonoyl-glycerol Suppresses Interferon-gamma Production in Phorbol Ester/ionomycin-activated Mouse Splenocytes Independent of CB1 or CB2. J Leukoc Biol. 2005;77(6):966-74. PubMed PMID: 15774549.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 2-Arachidonoyl-glycerol suppresses interferon-gamma production in phorbol ester/ionomycin-activated mouse splenocytes independent of CB1 or CB2. AU - Kaplan,Barbara L F, AU - Ouyang,Yanli, AU - Rockwell,Cheryl E, AU - Rao,Gautham K, AU - Kaminski,Norbert E, Y1 - 2005/03/17/ PY - 2005/3/19/pubmed PY - 2005/8/2/medline PY - 2005/3/19/entrez SP - 966 EP - 74 JF - Journal of leukocyte biology JO - J. Leukoc. Biol. VL - 77 IS - 6 N2 - 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-gamma (IFN-gamma) 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-gamma secretion. In addition, 2-AG suppressed IFN-gamma 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-gamma 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-gamma, 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-gamma production. Indeed, Io partially attenuated the 2-AG-induced suppression of PMA/Io-stimulated IFN-gamma production. Taken together, these data demonstrate that 2-AG suppresses IFN-gamma expression in murine splenocytes in a CB receptor-independent manner and that the mechanism partially involves suppression of intracellular calcium signaling and perturbation of NFAT nuclear translocation. SN - 0741-5400 UR - https://www.unboundmedicine.com/medline/citation/15774549/2_Arachidonoyl_glycerol_suppresses_interferon_gamma_production_in_phorbol_ester/ionomycin_activated_mouse_splenocytes_independent_of_CB1_or_CB2_ L2 - https://doi.org/10.1189/jlb.1104652 DB - PRIME DP - Unbound Medicine ER -