Di Marzo (1995) on biosynthesis of PEA

Vincenzo Di Marzo and his group explores PEA already since 2 decades, since professor Rita Levi-Montalcini first identified the mechanism of action of PEA.

They published their hallmark paper some years after Montalcini identified the mastcell as one of the important targets of PEA. At that time PEA was thought to be ligand of the Cannabinoid system, just as the most important endocannabinoid, anandamide was. Therefore they opened their paper with the following remark:

Anandamide (arachidonoylethanolamide, AnNH) and palmitoylethanolamide (PEA) have been proposed as the physiological ligands, respectively, of central and peripheral cannabinoid receptors. and:

Both of these receptors are expressed in immune cells, including macrophages and mast cells/basophils, where immunomodulatory and/or anti-inflammatory actions of Anandamide and PEA have been recently reported.

Because the main target of the biological action around 1995 was thought to be the white bloodcells, later we understood PEA is synthetized on demand in many body cells, from glia up to nerve cells to protect them against threads (ischemia for instance), they focussed on the metabolic happenings in the white blood cells.

They pointed out the importance of the finding of Montalcini et al in 1994 of the presence of the nerve growth factor in mast cells, and:

Among the receptor classes whose expression and function have been described in both the central nervous system and lymphoid tissues, increasing attention has been paid recently to cannabinoid receptors, particularly since members of a class of endogenous lipids, the acylethanolamides (AEs), have been proposed as their possible physiological ligands

Palmitoylethanolamide was the first aceylethanolamides discovered in 1957 by Kuehl et al. At that time, in the 90s it was logical to put so much emphasis on Cannabinoid receptors, as the CB1 receptor was just cloned and sequenced in 1990 and the second cannabinoid receptor, the CB2 receptor was discovered in 1993. One knew that the CB1 receptors were expressed also in the central nervous system ( as well as in peripheral tissues and cells), and CB2 receptors were at that time only known in immune tissue, and not in nervous system. So the picture seemed very crisp (later it proved to be wrong, just as wrong that the idea around the 90s that PEA was an endocannabinoid with high affinity of the CB2 receptor…).

Di Marzo further pointed out, based again on a paper from the Montalcini school in 1995 that PEA, which he still (wronly) charcterised as an endocannabinoid and a congener of anandamide, could:

1) to bind selectively to membrane preparations from rat basophilic leukemia (RBL-2H3) cells, where the CB2, but not the CB1, receptor was found to be expressed; and
2) to inhibit the immunogenic activation of RBL-2H3 and mast cells.

They also pointed out that anandamide did not exert the action number 2, but antagonized the effect induced by PEA. Di Marzo quoted the 1995 paper were the authors suggested that PEA, by acting at CB2 receptors, might function as an “autacoid local inflammation antagonist amide

Because still many questions were open as to how exactly PEA worked, and we qote Di Marzo:

Despite the well documented immunomodulatory actions of Anandamide and PEA, no report exists on the actual availability to leukocytes of molecular mechanisms for the formation and inactivation of these two Acylethanolamides, required to support their proposed role as either autacoid local inflammation antagonist amides or blood cell cannabinoid receptor endogenous ligands.

Hence the necessity to carry out the present study, where we show that two immortalized blood cell types, J774 and RBL-2H3 cells, widely used as experimental models for monocytes/macrophages and mast cells/basophils, possess the means for the biosynthesis, uptake, and degradation of Ananadamide and PEA.

Biosynthesis of PEA

Both RBL-2H3 cells and J774 macrophages were found here to biosynthesize both acylethanolamides anadamide and PEA when stimulated by an inducer of anandamide release, ionomycin. Immunogenic stimulation of RBL-2H3 cells, carried out under conditions leading to serotonin/histamine release, also caused the formation of Anandamide and PEA, albeit to a smaller extent.

The production of PEA and other aceylethanolamides showed that these lipids are biosynthesized through the pathway responsible for Acylethanolamide formation as was known already from studies in dog brain and heart, rat striatal/cortical neurons and testis, and mouse neuroblastoma cells, via the phospholipase D-catalyzed hydrolysis of the corresponding NaPEs.

In addition to be able to biosynthese anandamide and PEA, both J774 macrophages and RBL-2H3 cells were found in the Di marzo’s study to possess also the enzymes for the inactivation of the two anandamide and PEA.

Conclusion: PEA is an endogenous immunomodulator

Their conclusion was:

In conclusion, the present study, by describing at once the biosynthesis, uptake, and degradation of AnNH and PEA in J774 macrophages and RBL-2H3 basophils, has provided biochemical grounds to the previous hypothesis that these AEs may function as endogenous immunomodulators.

Studies aimed at clarifying further the molecular mode of action of AnNH and PEA on blood cells and investigating the regulation of the metabolic processes leading to leukocyte AE formation and degradation are now recommended in order to proceed toward a complete evaluation of this hypothesis.

Moreover, our findings may open the way to future investigations on the involvement of Ananadamide and PEA in the chemical signaling between basophils/macrophages and other cannabinoid receptor-containing and AE-synthesizing cells under physiopathological conditions.


Tiziana Bisogno, Stefano Maurelli, Dominique Melck, Luciano De Petrocellis and Vincenzo Di Marzo Biosynthesis, Uptake, and Degradation of Anandamide and Palmitoylethanolamide in Leukocytes
Source: doi: 10.1074/jbc.272.6.3315
February 7, 1997 The Journal of Biological Chemistry, 272, 3315-3323.

More info in PEA under this link

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