Influence of fatty acid ethanolamides and Δ9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells

Abstract

The effects of arachidonic acid ethanolamide (anandamide), palmitoylethanolamide and Δ 9-tetrahydrocannabinol on the production of tumor necrosis factor- α (TNF- α), interleukin-4, interleukin-6, interleukin-8, interleukin-10, interferon- γ, p55 and p75 TNF- α soluble receptors by stimulated human peripheral blood mononuclear cells as well as [ 3 H ]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- α, interferon- γ, interleukin-4 and p75 TNF- α soluble receptors at higher concentrations (0.3–3 μM). Palmitoylethanolamide inhibited interleukin-4, interleukin-6, interleukin-8 synthesis and the production of p75 TNF- α soluble receptors at concentrations similar to those of anandamide but failed to influence TNF- α and interferon- γ 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. Δ 9-Tetrahydrocannabinol exerted a biphasic action on pro-inflammatory cytokine production. TNF- α, interleukin-6 and interleukin-8 synthesis was maximally inhibited by 3 nM Δ 9-tetrahydrocannabinol but stimulated by 3 μM Δ 9-tetrahydrocannabinol, as was interleukin-8 and interferon- γ synthesis. The level of interleukin-4, interleukin-10 and p75 TNF- α soluble receptors was diminished by 3 μM Δ 9-tetrahydrocannabinol. [ 3 H ]Arachidonate release was stimulated only by high Δ 9-tetrahydrocannabinol and anandamide concentrations (30 μM). These results suggest that the inhibitory properties of anandamide, palmitoylethanolamide and Δ 9-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.