Glucocorticoids shift arachidonic acid metabolism toward endocannabinoid synthesis: a non-genomic anti-inflammatory switch

Abstract

Glucocorticoids are capable of exerting both genomic and non-genomic actions in target cells of multiple tissues, including the brain, which trigger an array of electrophysiological, metabolic, secretory and inflammatory regulatory responses. Here, we have attempted to show how glucocorticoids may generate a rapid anti-inflammatory response by promoting arachidonic acid-containing endocannabinoids biosynthesis. According to our hypothesized model, non-genomic action of glucocorticoids results in the global shift of membrane lipid metabolism, subverting metabolic pathways toward the synthesis of the anti-inflammatory endocannabinoids, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), and away from arachidonic acid production. Post-transcriptional inhibition of cyclooxygenase-2 (COX(2)) synthesis by glucocorticoids assists this mechanism by suppressing the synthesis of pro-inflammatory prostaglandins as well as endocannabinoid-derived prostanoids. In the central nervous system (CNS) this may represent a major neuroprotective system, which may cross-talk with leptin signaling in the hypothalamus allowing for the coordination between energy homeostasis and the inflammatory response.

Figure 1

Non-genomic and post-transcriptional glucocorticoid-mediated regulation of arachidonic acid and endocannabinoid metabolism. Enzymes stimulated or inhibited by glucocorticoids are shown in green and red, respectively. Glucocorticoids stimulate several enzymes that participate in the synthesis of different endocannabinoid precursors with concomitant inhibition of COX₂, preventing endocannabinoid metabolism into endocannabinoid-derived prostaglandins. On the other hand, by inhibiting both cPLA₂ and COX₂, glucocorticoids prevent the use of endocannabinoid precursors to form arachidonic acid, making them available for the synthesis of endocannabinoids. The overall effect, therefore, is to shift the arachidonic acid metabolism away from the synthesis of prostaglandins, promoting endocannabinoid formation. AA, arachidonic acid; AEA, arachidonoylethanolamide (anandamide); COX₂, cyclooxygenase 2; COX₁, cyclooxygenase 1; DAG, diacylglycerol; EEA, epoxyeicosatrienoic acid; HPETE, hydroperoxyeicosatetraenoic acids; LPA, lisophosphatidic; PA, phosphatidic acid; PC, phosphatidylcholine; PGH₂-EA, prostaglandin H2 ethanolamide; PGH₂, prostaglandin hydroxy-endoperoxide; PGH₂G, prostaglandin H₂ glycerol ester; PI, phosphatidylinositol; PIP, phosphatidylinositol phosphate; PKA, protein kinase A; PLA₁, phospholipase A₁; PLC, phospholipase C; PLD, phospholipase D; sPLA₂, secretory phospholipase A₂.