Biosynthesis of 15-deoxy-Δ12,14-PGJ2 and the ligation of PPARγ

Abstract

15-deoxy-Delta12,14-PGJ2 (15d-PGJ2) has been identified as an endogenous ligand for PPARgamma, inducing adipogenesis in vitro. Additional roles for this molecule in the propagation and resolution of inflammation, ligation of NF-kappaB, and mediation of apoptosis have been proposed. However, quantitative, physiochemical evidence for the formation of 15d-PGJ2 in vivo is lacking. We report that 15d-PGJ2 is detectable using liquid chromatography-mass spectrometry-mass spectrometry at low picomolar concentrations in the medium of 3T3-L1 preadipocytes. However, despite induction of COX-2, production of PGs, including 15d-PGJ2, does not increase during adipocyte differentiation, a process unaltered by COX inhibition. 15d-PGJ2 is detectable as a minor product of COX-2 in human urine. However, its biosynthesis is unaltered during or after COX activation in vivo by LPS. Furthermore, the biosynthesis of 15d-PGJ2 is not augmented in the joint fluid of patients with arthritis, nor is its urinary excretion increased in patients with diabetes or obesity. 15d-PGJ2 is not the endogenous mediator of PPARgamma-dependent adipocyte activation and is unaltered in clinical settings in which PPARgamma activation has been implicated.

Prostaglandin D2 and J2-series (PGJ2, Δ12-PGJ2) prostaglandins stimulate IL-6 and MCP-1, but inhibit leptin, expression and secretion by 3T3-L1 adipocytes

“…Adipocytes can synthesize and release prostaglandins, the key enzymes for synthesis from fatty acids being present [10,43]. The secretion of 15d-PGJ 2 by 3T3-L1 adipocytes has been reported [1], and both these cells and human adipose tissue express PGD 2 synthase [24]. Thus, PGD 2 and its derivatives can be derived directly from adipocytes and potentially act in a paracrine or autocrine manner in adipose tissue.…”

The anti-inflammatory prostaglandin 15d-PGJ2 decreases oxidative/nitrosative mediators in brain after acute stress in rats

“…One of its isoforms, PPARγ, exerts antiinflammatory activity in several tissues by regulating the expression of distinct inflammatory genes (Michalik and Wahli 1999). However, this mechanism seems not to explain all the effects of 15d-PGJ 2 (see review in Bell-Parikh et al 2003). An alternative mechanism for controlling gene expression, which has received much attention, is the interaction with several transcription factors including nuclear factor kappa B (NFκB), AP-1 and STAT-1 (Rossi et al 2000;Pérez-Sala et al 2003;Weber et al 2004), a situation that is likely to occur with NOS-2 in the stressed brain.…”

The cardinal role of the phospholipase A2/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E2 (PCPP) axis in inflammostasis

“…In vitro, 15d-PGJ 2 has been shown to directly deactivate the proinflammatory transcription factor nuclear factor-kappa B (NF-jB) [24,25]. Furthermore, 15d-PGJ 2 is often referred to as an endogenous ligand for nuclear receptor/transcription factor peroxisome proliferator-activated receptor (PPAR)-c [26]. 1 Other enzymes also participate in the production of PGE 2 .…”