title: Protective role of palmitoylethanolamide in contact allergic dermatitis.
abstract: 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.
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (Naples), Italy.
authors.forename: S
authors.initials: S
authors.lastname: Petrosino
authors.forename: L
authors.initials: L
authors.lastname: Cristino
authors.forename: M
authors.initials: M
authors.lastname: Karsak
authors.forename: E
authors.initials: E
authors.lastname: Gaffal
authors.forename: N
authors.initials: N
authors.lastname: Ueda
authors.forename: T
authors.initials: T
authors.lastname: Tüting
authors.forename: T
authors.initials: T
authors.lastname: Bisogno
authors.forename: D
authors.initials: D
authors.lastname: De Filippis
authors.forename: A
authors.initials: A
authors.lastname: D'Amico
authors.forename: C
authors.initials: C
authors.lastname: Saturnino
authors.forename: P
authors.initials: P
authors.lastname: Orlando
authors.forename: A
authors.initials: A
authors.lastname: Zimmer
authors.forename: T
authors.initials: T
authors.lastname: Iuvone
authors.forename: V
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: 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
chemical_list: 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