PMID- 16611855
OWN - NLM
STAT- MEDLINE
DCOM- 20061024
LR  - 20181201
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 70
IP  - 1
DP  - 2006 Jul
TI  - Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through 
      peroxisome proliferator-activated receptor gamma independently of cannabinoid 
      receptors 1 and 2.
PG  - 101-11
AB  - 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.
FAU - Rockwell, Cheryl E
AU  - Rockwell CE
AD  - Department of Pharmacology and Toxicology, Michigan State University, 315 
      National Food Safety and Toxicology Building, East Lansing, MI 48824-1317, USA.
FAU - Snider, Natasha T
AU  - Snider NT
FAU - Thompson, Jerry T
AU  - Thompson JT
FAU - Vanden Heuvel, John P
AU  - Vanden Heuvel JP
FAU - Kaminski, Norbert E
AU  - Kaminski NE
LA  - eng
GR  - DA12470/DA/NIDA NIH HHS/United States
GR  - DA15276/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20060412
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (15-deoxyprostaglandin J2)
RN  - 0 (Arachidonic Acids)
RN  - 0 (Benzamides)
RN  - 0 (Endocannabinoids)
RN  - 0 (Fatty Acid-Binding Proteins)
RN  - 0 (Glycerides)
RN  - 0 (Interleukin-2)
RN  - 0 (NF-kappa B)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (PPAR gamma)
RN  - 0 (Peroxisome Proliferator-Activated Receptors)
RN  - 0 (Pyridines)
RN  - 0 (Receptor, Cannabinoid, CB1)
RN  - 0 (Receptor, Cannabinoid, CB2)
RN  - 0 (T 0070907)
RN  - 0 (Thiazolidinediones)
RN  - 207137-56-2 (Interleukin-4)
RN  - 82115-62-6 (Interferon-gamma)
RN  - 8D239QDW64 (glyceryl 2-arachidonate)
RN  - RXY07S6CZ2 (Prostaglandin D2)
RN  - U8QXS1WU8G (ciglitazone)
SB  - IM
MH  - 3T3-L1 Cells
MH  - Adipogenesis/drug effects
MH  - Animals
MH  - Arachidonic Acids/chemistry/*pharmacology
MH  - Benzamides/pharmacology
MH  - Cells, Cultured
MH  - Endocannabinoids
MH  - Fatty Acid-Binding Proteins/genetics
MH  - Female
MH  - Gene Expression/drug effects
MH  - Glycerides/chemistry/*pharmacology
MH  - Humans
MH  - Interferon-gamma/genetics
MH  - Interleukin-2/antagonists & inhibitors/*metabolism
MH  - Interleukin-4/genetics
MH  - Jurkat Cells
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - NF-kappa B/metabolism
MH  - NFATC Transcription Factors/metabolism
MH  - PPAR gamma/genetics/*metabolism
MH  - Peroxisome Proliferator-Activated Receptors/genetics
MH  - Prostaglandin D2/analogs & derivatives/pharmacology
MH  - Protein Binding/drug effects
MH  - Pyridines/pharmacology
MH  - Receptor, Cannabinoid, CB1/genetics/*physiology
MH  - Receptor, Cannabinoid, CB2/genetics/*physiology
MH  - Response Elements/genetics
MH  - T-Lymphocytes/cytology/drug effects/metabolism
MH  - Thiazolidinediones/pharmacology
EDAT- 2006/04/14 09:00
MHDA- 2006/10/25 09:00
CRDT- 2006/04/14 09:00
PHST- 2006/04/14 09:00 [pubmed]
PHST- 2006/10/25 09:00 [medline]
PHST- 2006/04/14 09:00 [entrez]
AID - mol.105.019117 [pii]
AID - 10.1124/mol.105.019117 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2006 Jul;70(1):101-11. doi: 10.1124/mol.105.019117. Epub 2006 Apr 
      12.