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Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor gamma independently of cannabinoid receptors 1 and 2.
Mol Pharmacol 2006; 70(1):101-11MP

Abstract

2-Arachidonyl glycerol (2-AG) is an endogenous arachidonic acid derivative that binds cannabinoid receptors CB1 and CB2 and is hence termed an endocannabinoid. 2-AG also modulates a variety of immunological responses, including expression of the autocrine/paracrine T cell growth factor interleukin (IL)-2. The objective of the present studies was to determine the mechanism responsible for IL-2 suppression by 2-AG. Because of the labile properties of 2-AG, 2-AG ether, a nonhydrolyzable analog of 2-AG, was also used. Both 2-AG and 2-AG ether suppressed IL-2 expression independently of CB1 and CB2, as demonstrated in leukocytes derived from CB1/CB2-null mice. Moreover, we demonstrated that both 2-AG and 2-AG ether treatment activated peroxisome proliferator-activated receptor gamma (PPARgamma), as evidenced by forced differentiation of 3T3-L1 cells into adipocytes, induction of aP2 mRNA levels, and activation of a PPARgamma-specific luciferase reporter in transiently transfected 3T3-L1 cells. Consequently, the putative role of PPARgamma in IL-2 suppression by 2-AG and 2-AG ether was examined in Jurkat T cells. Concordant with PPARgamma involvement, the PPARgamma-specific antagonist 2-chloro-5-nitro-N-(4-pyridyl)-benzamide (T0070907) blocked 2-AG- and 2-AG ether-mediated IL-2 suppression. Likewise, 2-AG suppressed the transcriptional activity of two transcription factors crucial for IL-2 expression, nuclear factor of activated T cells and nuclear factor kappaB, in the absence but not in the presence of T0070907. 2-AG treatment also induced PPARgamma binding to a PPAR response element in activated Jurkat T cells. Together, the aforementioned studies identify PPARgamma as a novel intracellular target of 2-AG, which mediates the suppression of IL-2 by 2-AG in a manner that is independent of CB1 and/or CB2.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Michigan State University, 315 National Food Safety and Toxicology Building, East Lansing, MI 48824-1317, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16611855

Citation

Rockwell, Cheryl E., et al. "Interleukin-2 Suppression By 2-arachidonyl Glycerol Is Mediated Through Peroxisome Proliferator-activated Receptor Gamma Independently of Cannabinoid Receptors 1 and 2." Molecular Pharmacology, vol. 70, no. 1, 2006, pp. 101-11.
Rockwell CE, Snider NT, Thompson JT, et al. Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor gamma independently of cannabinoid receptors 1 and 2. Mol Pharmacol. 2006;70(1):101-11.
Rockwell, C. E., Snider, N. T., Thompson, J. T., Vanden Heuvel, J. P., & Kaminski, N. E. (2006). Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor gamma independently of cannabinoid receptors 1 and 2. Molecular Pharmacology, 70(1), pp. 101-11.
Rockwell CE, et al. Interleukin-2 Suppression By 2-arachidonyl Glycerol Is Mediated Through Peroxisome Proliferator-activated Receptor Gamma Independently of Cannabinoid Receptors 1 and 2. Mol Pharmacol. 2006;70(1):101-11. PubMed PMID: 16611855.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor gamma independently of cannabinoid receptors 1 and 2. AU - Rockwell,Cheryl E, AU - Snider,Natasha T, AU - Thompson,Jerry T, AU - Vanden Heuvel,John P, AU - Kaminski,Norbert E, Y1 - 2006/04/12/ PY - 2006/4/14/pubmed PY - 2006/10/25/medline PY - 2006/4/14/entrez SP - 101 EP - 11 JF - Molecular pharmacology JO - Mol. Pharmacol. VL - 70 IS - 1 N2 - 2-Arachidonyl glycerol (2-AG) is an endogenous arachidonic acid derivative that binds cannabinoid receptors CB1 and CB2 and is hence termed an endocannabinoid. 2-AG also modulates a variety of immunological responses, including expression of the autocrine/paracrine T cell growth factor interleukin (IL)-2. The objective of the present studies was to determine the mechanism responsible for IL-2 suppression by 2-AG. Because of the labile properties of 2-AG, 2-AG ether, a nonhydrolyzable analog of 2-AG, was also used. Both 2-AG and 2-AG ether suppressed IL-2 expression independently of CB1 and CB2, as demonstrated in leukocytes derived from CB1/CB2-null mice. Moreover, we demonstrated that both 2-AG and 2-AG ether treatment activated peroxisome proliferator-activated receptor gamma (PPARgamma), as evidenced by forced differentiation of 3T3-L1 cells into adipocytes, induction of aP2 mRNA levels, and activation of a PPARgamma-specific luciferase reporter in transiently transfected 3T3-L1 cells. Consequently, the putative role of PPARgamma in IL-2 suppression by 2-AG and 2-AG ether was examined in Jurkat T cells. Concordant with PPARgamma involvement, the PPARgamma-specific antagonist 2-chloro-5-nitro-N-(4-pyridyl)-benzamide (T0070907) blocked 2-AG- and 2-AG ether-mediated IL-2 suppression. Likewise, 2-AG suppressed the transcriptional activity of two transcription factors crucial for IL-2 expression, nuclear factor of activated T cells and nuclear factor kappaB, in the absence but not in the presence of T0070907. 2-AG treatment also induced PPARgamma binding to a PPAR response element in activated Jurkat T cells. Together, the aforementioned studies identify PPARgamma as a novel intracellular target of 2-AG, which mediates the suppression of IL-2 by 2-AG in a manner that is independent of CB1 and/or CB2. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/16611855/Interleukin_2_suppression_by_2_arachidonyl_glycerol_is_mediated_through_peroxisome_proliferator_activated_receptor_gamma_independently_of_cannabinoid_receptors_1_and_2_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16611855 DB - PRIME DP - Unbound Medicine ER -