INFLUENCE OF FATTY-ACID ETHANOLAMIDES AND DELTA(9)-TETRAHYDROCANNABINOL ON CYTOKINE AND ARACHIDONATE RELEASE BY MONONUCLEAR-CELLS

The effects of arachidonic acid ethanolamide (anandamide), palmitoylet hanolamide and Delta(9)-tetrahydrocannabinol on the production of tumo r necrosis factor-alpha (TNF-alpha), interleukin-4, interleukin-6, int erleukin-8, interleukin-10, interferon-gamma, p55 and p75 TNF-alpha so luble receptors by stimulated human peripheral blood mononuclear cells as well as [H-3]arachidonic acid release by non-stimulated and N-form yl-Met-Leu-Phe (fMLP)-stimulated human monocytes were investigated. An andamide was shown to diminish interleukin-6 and interleukin-8 product ion at low nanomolar concentrations (3-30 nM) but inhibited the produc tion of TNF-alpha, interferon-gamma, interleukin-4 and p75 TNF-alpha s oluble receptors at higher concentrations (0.3-3 mu M). Palmitoylethan olamide inhibited interleukin-4, interleukin-6, interleukin-8 synthesi s and the production of p75 TNF-alpha soluble receptors at concentrati ons similar to those of anandamide but failed to influence TNF-alpha a nd interferon-gamma production. The effect of both compounds on interl eukin-6 and interleukin-8 production disappeared with an increase in t he concentration used. Neither anandamide nor palmitoylethanolamide in fluenced interleukin-10 synthesis. Delta(9)-Tetrahydrocannabinol exert ed a biphasic action on pro-inflammatory cytokine production. TNF-alph a, interleukin-6 and interleukin-8 synthesis was maximally inhibited b y 3 nM Delta(9)-tetrahydrocannabinol but stimulated by 3 mu M Delta(9) -tetrahydrocannabinol, as was interleukin-8 and interferon-gamma synth esis. The level of interleukin-4, interleukin-10 and p75 TNF-alpha sol uble receptors was diminished by 3 mu M Delta(9)-tetrahydrocannabinol. [H-3]Arachidonate release was stimulated only by high Delta(9)-tetrah ydrocannabinol and anandamide concentrations (30 mu M) These results s uggest that the inhibitory properties of anandamide, palmitoylethanola mide and Delta(9)-tetrahydrocannabinol are determined by the activatio n of the peripheral-type cannabinoid receptors, and that various endog enous fatty acid ethanolamides may participate in the regulation of th e immune response. (C) 1997 Elsevier Science B.V.