Role for PPARγ in IL-2 inhibition in T cells by Echinacea-derived undeca-2E-ene-8,10-diynoic acid isobutylamide

Certain fatty acid amides from Echinacea spp. have demonstrated moderate to high cannabinoid activity. As a result, CB2 activation is currently hypothesized to be the basis of activity for immunomodulation by Echinacea spp. PPARγ, an orphan nuclear receptor and lipid sensor, is known to inhibit IL-2 production and be activated by fatty acid derivatives such as the endocannabinoids. In these investigations, we demonstrate that undeca-2E-ene-8,10-diynoic acid, an Echinacea angustifolia-derived alkylamide lacking affinity for the CB2 receptor, inhibits IL-2 secretion in Jurkat T cells through PPARγ activity at low micromolar concentrations (330 ng/mL). The IL-2 inhibition is reversed by the addition of the selective PPARγ antagonist T0070907. Additionally, we show that that undeca-2-ene-8,10-diynoic acid stimulates 3T3-L1 differentiation, a process dependent on PPARγ activity. These experiments demonstrate that PPARγ is involved in T cell IL-2 inhibition by undeca-2-ene-8,10-diynoic acid and suggest that cytokine modulation by the alkylamides is due to polyvalent activity.