Influence of fatty acid ethanolamides and delta9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells.
The effects of arachidonic acid ethanolamide (anandamide), palmitoylethanolamide and delta9-tetrahydrocannabinol on the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-4, interleukin-6, interleukin-8, interleukin-10, interferon-gamma, p55 and p75 TNF-alpha soluble receptors by stimulated human peripheral blood mononuclear cells as well as [3H]arachidonic acid release by non-stimulated and N-formyl-Met-Leu-Phe (fMLP)-stimulated human monocytes were investigated. Anandamide was shown to diminish interleukin-6 and interleukin-8 production at low nanomolar concentrations (3-30 nM) but inhibited the production of TNF-alpha, interferon-gamma, interleukin-4 and p75 TNF-alpha soluble receptors at higher concentrations (0.3-3 microM). Palmitoylethanolamide inhibited interleukin-4, interleukin-6, interleukin-8 synthesis and the production of p75 TNF-alpha soluble receptors at concentrations similar to those of anandamide but failed to influence TNF-alpha and interferon-gamma production. The effect of both compounds on interleukin-6 and interleukin-8 production disappeared with an increase in the concentration used. Neither anandamide nor palmitoylethanolamide influenced interleukin-10 synthesis. delta9-Tetrahydrocannabinol exerted a biphasic action on pro-inflammatory cytokine production. TNF-alpha, interleukin-6 and interleukin-8 synthesis was maximally inhibited by 3 nM delta9-tetrahydrocannabinol but stimulated by 3 microM delta9-tetrahydrocannabinol, as was interleukin-8 and interferon-gamma synthesis. The level of interleukin-4, interleukin-10 and p75 TNF-alpha soluble receptors was diminished by 3 microM delta9-tetrahydrocannabinol. [3H]Arachidonate release was stimulated only by high delta9-tetrahydrocannabinol and anandamide concentrations (30 microM). These results suggest that the inhibitory properties of anandamide, palmitoylethanolamide and delta9-tetrahydrocannabinol are determined by the activation of the peripheral-type cannabinoid receptors, and that various endogenous fatty acid ethanolamides may participate in the regulation of the immune response.
Berdyshev
E V
EV
Institute of Marine Biology, Vladivostok, Russia.
Boichot
E
E
Germain
N
N
Allain
N
N
Anger
J P
JP
Lagente
V
V
D000577:Amides; D016718:Arachidonic Acid / Q000097:blood / Q000378:metabolism*; D001095:Arachidonic Acids / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology*; D063388:Endocannabinoids; D004983:Ethanolamines; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism*; D010169:Palmitic Acids / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D012636:Secretory Rate / Q000187:drug effects
D000577:Amides; D001095:Arachidonic Acids; D016207:Cytokines; D063388:Endocannabinoids; D004983:Ethanolamines; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; D016718:Arachidonic Acid; C005958:palmidrol; D013759:Dronabinol; C078814:anandamide