title: Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor gamma independently of cannabinoid receptors 1 and 2.
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.affiliation: Department of Pharmacology and Toxicology, Michigan State University, 315 National Food Safety and Toxicology Building, East Lansing, MI 48824-1317, USA.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Rockwell
authors.forename: Natasha T
authors.initials: NT
authors.lastname: Snider
authors.forename: Jerry T
authors.initials: JT
authors.lastname: Thompson
authors.forename: John P
authors.initials: JP
authors.lastname: Vanden Heuvel
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D063388:Endocannabinoids; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005989:Glycerides / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000502:physiology*; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000502:physiology*; D020218:Response Elements / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C477819:15-deoxyprostaglandin J2; D001095:Arachidonic Acids; D001549:Benzamides; D063388:Endocannabinoids; D050556:Fatty Acid-Binding Proteins; D005989:Glycerides; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C458508:T 0070907; D045162:Thiazolidinediones; D015847:Interleukin-4; D007371:Interferon-gamma; C094503:glyceryl 2-arachidonate; D015230:Prostaglandin D2; C039671:ciglitazone