Protective role of palmitoylethanolamide in contact allergic dermatitis.
BACKGROUND
Palmitoylethanolamide (PEA) is an anti-inflammatory mediator that enhances the activation by anandamide (AEA) of cannabinoid receptors and transient receptor potential vanilloid type-1 (TRPV1) channels, and directly activates peroxisome proliferator-activated receptor-alpha (PPAR-alpha). In mice, 2,4-dinitrofluorobenzene (DNFB)-induced contact allergic dermatitis (CAD) in inflamed ears is partly mediated by the chemokine Monocyte Chemotactic Protein-2 (MCP-2) and accompanied by elevation of AEA levels. No datum is available on PEA regulation and role in CAD.


OBJECTIVE
We examined whether PEA is produced during DNFB-induced CAD, and if it has any direct protective action in keratinocytes in vitro.


METHODS
Eight- to ten-week-old female C57BL/6J wild-type and CB(1)/CB(2) double knock-out mice were used to measure PEA levels and the expression of TRPV1, PPAR-alpha receptors and enzymes responsible for PEA biosynthesis and degradation. Human keratinocytes (HaCaT) cells were stimulated with polyinosinic polycytidylic acid [poly-(I:C)], and the expression and release of MCP-2 were measured in the presence of PEA and antagonists of its proposed receptors.


RESULTS
2,4-Dinitrofluorobenzene increased ear skin PEA levels and up-regulated TRPV1, PPAR-alpha and a PEA-biosynthesizing enzyme in ear keratinocytes. In HaCaT cells, stimulation with poly-(I:C) elevated the levels of both PEA and AEA, and exogenous PEA (10 microM) inhibited poly-(I:C)-induced expression and release of MCP-2 in a way reversed by antagonism at TRPV1, but not PPAR-alpha. PEA (5-10 mg/kg, intraperitoneal) also inhibited DNFB-induced ear inflammation in mice in vivo, in a way attenuated by TRPV1 antagonism.


CONCLUSIONS
We suggest that PEA is an endogenous protective agent against DNFB-induced keratinocyte inflammation and could be considered for therapeutic use against CAD.
Petrosino
S
S
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (Naples), Italy.
Cristino
L
L
Karsak
M
M
Gaffal
E
E
Ueda
N
N
Tüting
T
T
Bisogno
T
T
De Filippis
D
D
D'Amico
A
A
Saturnino
C
C
Orlando
P
P
Zimmer
A
A
Iuvone
T
T
Di Marzo
V
V
D000577:Amides; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000032:analysis; D000894:Anti-Inflammatory Agents, Non-Steroidal; D017449:Dermatitis, Allergic Contact / Q000209:etiology / Q000378:metabolism*; D004139:Dinitrofluorobenzene; D063388:Endocannabinoids; D004983:Ethanolamines; D005260:Female; D007249:Inflammation / Q000276:immunology; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010169:Palmitic Acids / Q000032:analysis* / Q000276:immunology; D020011:Protective Agents
D000577:Amides; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D063388:Endocannabinoids; D004983:Ethanolamines; D010169:Palmitic Acids; D020011:Protective Agents; C005958:palmidrol; D004139:Dinitrofluorobenzene