Interleukin-2 Suppression by 2-Arachidonyl Glycerol Is Mediated through Peroxisome Proliferator-Activated Receptor γ 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 ␥ (PPAR␥), as evidenced by forced differentiation of 3T3-L1 cells into adipocytes, induction of aP2 mRNA levels, and activation of a PPAR␥-specific luciferase reporter in transiently transfected 3T3-L1 cells. Consequently, the putative role of PPAR␥ in IL-2 suppression by 2-AG and 2-AG ether was examined in Jurkat T cells. Concordant with PPAR␥ involvement, the PPAR␥-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 B, in the absence but not in the presence of T0070907. 2-AG treatment also induced PPAR␥ binding to a PPAR response element in activated Jurkat T cells. Together, the aforementioned studies identify PPAR␥ 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.

Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6

“…However, it also is a known substrate for the COX and lipoxygenase enzymes (19,21,38). Some of the effects of 2-AG have been shown to be mediated by some of its metabolites, such as arachidonic acid and its PG derivatives, or through the action of 2-AG on the PPARs (10,19,(39)(40)(41). Although it is known that PG-Gs constitute COX-derived 2-AG metabolites, their effects are not well documented.…”

Mitochondria: a possible nexus for the regulation of energy homeostasis by the endocannabinoid system?

“…The resulting PPAR-RXR heterodimers function as transcriptional regulators of lipid metabolism, energy balance, and insulin sensitivity (3, 99). Importantly, a number of natural and synthetic cannabinoids (including AEA, 2-AG, Win55,212, HU210, ⌬9-THC) have been shown to directly bind to and regulate the activity of PPAR isoforms (14,101,120). Notably, PPAR activation has been shown to convey a number of beneficial effects on lipid metabolism that may be mediated through enhanced mitochondrial fatty acid oxidation (36,48,92,114,121,139).…”

Cannabinoid activation of peroxisome proliferator‐activated receptors: an update and review of the physiological relevance

“…2-AG also inhibits IL-2 secretion through the suppression of pro-inflammatory transcription factors, sensitive to PPARγ antagonism. 44 More recently, 2-AG was found to decrease the expression of COX-2 in response to IL1β or LPS, which were sensitive to PPARγ antagonism. 45 The 2-AG metabolite 15-deoxy-12,31 -PGJ(2)-glycerol ester also has anti-inflammatory actions mediated by PPARγ , 51 so the effects of 2-AG on PPARγ may be due to both activation by 2-AG itself and/or by its metabolites.…”