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Title: Inhibition of leukocyte function and interleukin-2 gene expression by 2-methylarachidonyl-(2'-fluoroethyl)amide, a stable congener of the endogenous cannabinoid receptor ligand anandamide

Abstract

Arachidonylethanolamide (anandamide, AEA) has been identified as an endogenous ligand for cannabinoid receptors CB1 and CB2. Characterization of the direct cannabimimetic actions of anandamide has been hampered by its short duration of action and rapid degradation in in vivo and in vitro systems to arachidonic acid, a precursor in the biosynthesis of a broad range of biologically active molecules. In the present studies, we utilized 2-methylarachidonyl-(2'-fluoroethyl)amide (F-Me-AEA), an analog of anandamide resistant to enzymatic degradation, to determine whether F-Me-AEA modulated T cell function similar to that of plant-derived cannabinoids. Indeed, F-Me-AEA at low micromolar concentrations exhibited a marked inhibition of phorbol ester plus calcium ionophore (PMA/Io)-induced IL-2 protein secretion and steady state mRNA expression. Likewise, a modest suppression of the mixed lymphocyte response was observed in the presence of F-Me-AEA indicating an alteration in T cell responsiveness to allogeneic MHC class II antigens. F-Me-AEA was also found to modestly inhibit forskolin-stimulated adenylate cyclase activity in thymocytes and splenocytes, a hallmark of cannabinoid receptor agonists. Further characterization of the influence of F-Me-AEA on the cAMP signaling cascade revealed an inhibition of CREB-1/ATF-1 phosphorylation and subsequently, an inhibition of CRE DNA binding activity. Characterization of nuclear binding proteins further revealed that NF-ATmore » and, to a lesser extent, NF-{kappa}B DNA binding activities were also suppressed. These studies demonstrate that F-Me-AEA modulates T cell function in a similar manner to plant-derived and endogenous cannabinoids and therefore can be utilized as an amidase- and hydrolysis-resistant endogenous cannabinoid.« less

Authors:
 [1];  [1];  [1];  [2];  [3];  [1]
  1. Department of Pharmacology and Toxicology and Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824 (United States)
  2. Department of Biochemistry, College of Medicine, Inje University, Pusan 614-735 (Korea, Republic of)
  3. Organix Inc., Woburn, MA 01801 (United States)
Publication Date:
OSTI Identifier:
20721811
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 205; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2004.09.013; PII: S0041-008X(04)00452-1; Copyright (c) 2004 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADENOSINE; AMP; ARACHIDONIC ACID; BRAIN; CALVES; DNA; ENZYME IMMUNOASSAY; ENZYMES; FLUORIDES; GLYCEROL; HYDROLYSIS; IMMUNOGLOBULINS; INHIBITION; LYMPHOCYTES; POLYMERASE CHAIN REACTION; RECEPTORS

Citation Formats

Kaplan, Barbara L.F., Yanli, Ouyang, Herring, Amy, Yea, Sung Su, Razdan, Raj, and Kaminski, Norbert E. Inhibition of leukocyte function and interleukin-2 gene expression by 2-methylarachidonyl-(2'-fluoroethyl)amide, a stable congener of the endogenous cannabinoid receptor ligand anandamide. United States: N. p., 2005. Web. doi:10.1016/j.taap.2004.09.013.
Kaplan, Barbara L.F., Yanli, Ouyang, Herring, Amy, Yea, Sung Su, Razdan, Raj, & Kaminski, Norbert E. Inhibition of leukocyte function and interleukin-2 gene expression by 2-methylarachidonyl-(2'-fluoroethyl)amide, a stable congener of the endogenous cannabinoid receptor ligand anandamide. United States. https://doi.org/10.1016/j.taap.2004.09.013
Kaplan, Barbara L.F., Yanli, Ouyang, Herring, Amy, Yea, Sung Su, Razdan, Raj, and Kaminski, Norbert E. 2005. "Inhibition of leukocyte function and interleukin-2 gene expression by 2-methylarachidonyl-(2'-fluoroethyl)amide, a stable congener of the endogenous cannabinoid receptor ligand anandamide". United States. https://doi.org/10.1016/j.taap.2004.09.013.
@article{osti_20721811,
title = {Inhibition of leukocyte function and interleukin-2 gene expression by 2-methylarachidonyl-(2'-fluoroethyl)amide, a stable congener of the endogenous cannabinoid receptor ligand anandamide},
author = {Kaplan, Barbara L.F. and Yanli, Ouyang and Herring, Amy and Yea, Sung Su and Razdan, Raj and Kaminski, Norbert E},
abstractNote = {Arachidonylethanolamide (anandamide, AEA) has been identified as an endogenous ligand for cannabinoid receptors CB1 and CB2. Characterization of the direct cannabimimetic actions of anandamide has been hampered by its short duration of action and rapid degradation in in vivo and in vitro systems to arachidonic acid, a precursor in the biosynthesis of a broad range of biologically active molecules. In the present studies, we utilized 2-methylarachidonyl-(2'-fluoroethyl)amide (F-Me-AEA), an analog of anandamide resistant to enzymatic degradation, to determine whether F-Me-AEA modulated T cell function similar to that of plant-derived cannabinoids. Indeed, F-Me-AEA at low micromolar concentrations exhibited a marked inhibition of phorbol ester plus calcium ionophore (PMA/Io)-induced IL-2 protein secretion and steady state mRNA expression. Likewise, a modest suppression of the mixed lymphocyte response was observed in the presence of F-Me-AEA indicating an alteration in T cell responsiveness to allogeneic MHC class II antigens. F-Me-AEA was also found to modestly inhibit forskolin-stimulated adenylate cyclase activity in thymocytes and splenocytes, a hallmark of cannabinoid receptor agonists. Further characterization of the influence of F-Me-AEA on the cAMP signaling cascade revealed an inhibition of CREB-1/ATF-1 phosphorylation and subsequently, an inhibition of CRE DNA binding activity. Characterization of nuclear binding proteins further revealed that NF-AT and, to a lesser extent, NF-{kappa}B DNA binding activities were also suppressed. These studies demonstrate that F-Me-AEA modulates T cell function in a similar manner to plant-derived and endogenous cannabinoids and therefore can be utilized as an amidase- and hydrolysis-resistant endogenous cannabinoid.},
doi = {10.1016/j.taap.2004.09.013},
url = {https://www.osti.gov/biblio/20721811}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 205,
place = {United States},
year = {Wed Jun 01 00:00:00 EDT 2005},
month = {Wed Jun 01 00:00:00 EDT 2005}
}